Therapeutic Methods

ABSTRACT

The present invention features a method for the treatment of Hepatitis C in a human in need thereof comprising administering a compound of Formulas (II) or (IIB) described herein or a pharmaceutically acceptable salt thereof in combination with one or more alternative Hepatitis C therapeutic agents.

CROSS-REFERENCE TO RELATED PATENTS AND PATENT APPLICATIONS

This is a Patent Cooperation Treaty application and claims the benefitof U.S. Provisional Application No. 61/524,429, filed Aug. 17, 2011 andU.S. Provisional Application No. 61/526,787, filed Aug. 24, 2011, bothof which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods for the treatment of viralinfections mediated by a member of the Flaviviridae family of virusessuch as Hepatitis C virus (HCV), and to compositions for such treatment,and more particularly to methods for the treatment of Hepatitis C insubjects needing such treatment comprising administering a benzofuranNS5B polymerase inhibitor described herein in combination with one ormore alternative therapeutic agents and to compositions andpharmaceutical compositions comprising a benzofuran NS5B polymeraseinhibitor described herein in combination with one or more alternativetherapeutic agents.

BACKGROUND OF THE INVENTION

Chronic infection with HCV is a major health problem associated withincreased risk for chronic liver disease, cirrhosis, hepatocellularcarcinoma, and liver failure. HCV is a hepacivirus member of theFlaviviridae family of RNA viruses that affect animals and humans. Thegenome is a single ˜9.6-kilobase strand of RNA, and consists of one openreading frame that encodes for a polyprotein of ˜3000 amino acidsflanked by untranslated regions at both 5′ and 3′ ends (5′- and 3′-UTR).The polyprotein serves as the precursor to at least 10 separate viralproteins critical for replication and assembly of progeny viralparticles. The organization of structural and non-structural proteins inthe HCV polyprotein is as follows:C-E1-E2-p7-N52-N53-NS4a-NS4b-NS5a-NS5b. Because the replicative cycle ofHCV does not involve any DNA intermediate and the virus is notintegrated into the host genome, HCV infection can theoretically becured. While the pathology of HCV infection affects mainly the liver,the virus is found in other cell types in the body including peripheralblood lymphocytes.

HCV is the major causative agent for post-transfusion and for sporadichepatitis. Infection by HCV is insidious in a high proportion ofchronically infected (and infectious) carriers who may not experienceclinical symptoms for many years. An estimated 170 million chroniccarriers worldwide are at risk of developing liver disease. See, forexample, Szabo, et al., Pathol. Oncol. Res. 2003, 9:215-221, andHoofnagle J H, Hepatology 1997, 26:15S-20S. In the United States alone2.7 million are chronically infected with HCV, and the number ofHCV-related deaths in 2000 was estimated between 8,000 and 10,000, anumber that is expected to increase significantly over the next years.

Historically, the standard treatment for chronic HCV was interferonalpha (IFN-alpha), particularly, pegylated interferon (PEG-IFN) alpha,in combination with ribavirin, which required six to twelve months oftreatment. This combination regimen included 48 weekly injections ofinterferon and daily doses of oral ribavirin HCV patients infected withthe genotype 1 virus.

IFN-alpha belongs to a family of naturally occurring small proteins withcharacteristic biological effects such as antiviral, immunoregulatory,and antitumoral activities. Interferons are produced and secreted bymost animal nucleated cells in response to several diseases, inparticular viral infections. IFN-alpha is an important regulator ofgrowth and differentiation affecting cellular communication andimmunological control. Treatment of HCV with interferon has frequentlybeen associated with adverse side effects such as fatigue, fever,chills, headache, myalgias, arthralgias, mild alopecia, psychiatriceffects and associated disorders, autoimmune phenomena and associateddisorders and thyroid dysfunction.

Ribavirin, an inhibitor of inosine 5′-monophosphate dehydrogenase(IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV.Despite the introduction of ribavirin, more than 50% of the patients donot eliminate the virus with the current standard therapy ofinterferon-alpha (IFN) and ribavirin. Also, a number of patients stillhave significant side effects related to ribavirin. Ribavirin causessignificant hemolysis in 10-20% of patients treated at currentlyrecommended doses, and the drug is both teratogenic and embryotoxic.

A number of additional approaches are being pursued to combat the virus.These include, for example, application of antisense oligonucleotides orribozymes for inhibiting HCV replication. Furthermore, low-molecularweight compounds that directly inhibit HCV proteins and interfere withviral replication are considered as attractive strategies to control HCVinfection. Among the viral targets, the NS3/4A protease/helicase, theNS5B RNA-dependent RNA polymerase, and the non-structural NS5A protein,are considered the most promising HCV viral targets for new drugs.Indeed, compounds said to be useful for treating HCV infections aredisclosed, for example, in WO2005/051318 (Chunduru, et al.) andWO2009/023179 (Schmitz, et al.). These references disclose methods forpreparing the compounds, compositions comprising the compounds,compositions comprising the compounds and additional compounds, andmethods of treating HCV.

Recently, two HCV therapeutic drugs have been approved in the US; eachused as 3-way combination therapies in conjunction with pegylatedinterferon and ribavirin. These are Vertex's and Johnson and Johnson'sNS3/4A protease inhibitor, Incivek® (telaprevir) and Merck's NS3/4Aprotease inhibitor, Victrelis® (boceprevir). The older 2-way pegylatedinterferon and ribavirin treatment regimen for HCV only cured about 40%of genotype 1 infected patients. Adding Victrelis® to that regimenshortens treatment duration for some and improves cure rates to morethan 60%. Likewise, adding Incivek® to that regimen shortens treatmentand boosts cure rates to as high as 80%. Unfortunately, neitherVictrelis® nor Incivek® can be used alone without also including thepegylated interferon and ribavirin regimen, which brings along theirconcomitant unfavorable side effect profiles. These protease inhibitorsalso are associated with additional side effects such as rash andincreased neutropenia. Such single active agent drugs also increase therisk of selecting for particular HCV mutations within the patient'sbody, which are resistant to these protease inhibitors.

Even with these recent improvements, a substantial fraction of patientsdo not respond with a sustained reduction in viral load and there is aclearly a need for more effective antiviral therapy of HCV infection.Therefore, what is needed is a combination therapy strategy to combatthe HCV virus without having to include the problematic pegylatedinterferon and ribavirin therapeutics. Multiple combination therapiesthat include Direct-acting antivirals (DAA) targeted to more than oneparticular type of HCV protein could reduce the incidence of sideeffects. Just as importantly, DAAs could reduce the virus's ability tomutate within the patient's body, which can lead to a resurgence of HCVviral titer.

In view of the worldwide epidemic level of HCV, the limited treatmentoptions available, and the need to expand access to all oral DAAregimens, there is a an ever growing need for new effective drugs fortreating chronic HCV infections.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the present invention, there isprovided a method for the treatment of Hepatitis C in a human in needthereof comprising administering a compound of Formula (II) or (IIB)described herein or a pharmaceutically acceptable salt thereof incombination with one or more alternative therapeutic Hepatitis C agents.

Compounds of Formulas (II) and (IIB), in which the boron-containing ringis directly linked to the sulfonamide, demonstrate increased metabolicstability compared to compounds of PCT/US2011/024822 (WO2011/103063) andPCT/US2011/024824 (WO2012/067663) in which the boron-containing ring islinked via an alkylene linker.

DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS

The present invention provides a method of treatment of Hepatitis CVirus (HCV) in a human in need thereof comprising administering acompound of Formula (II):

wherein:

R is independently selected from the group consisting of halogen,C₁₋₆alkyl, alkoxy, —CN, —CF₃, —O—C₆₋₁₀aryl optionally substituted byhalogen, and —O-heteroaryl optionally substituted by halogen;

R¹ is —C(O)OH, —C(O)NHR⁵ or heterocyclyl;

R² is C₁₋₆alkyl, C₃₋₆cycloalkyl, —C(H)F₂, —CF₃, or —OR⁶;

R³ is —S(O)₂R⁷ or —C(O)R⁷;

R⁴ is

(a) heteroaryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, hydroxy, hydroxyalkyl, aminoalkyl,—C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶,—NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl;

(b) C₆₋₁₀aryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, hydroxy, hydroxyalkyl, aminoalkyl,—C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶,—NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH,—C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to11-membered bicyclic heterocyclic ring system any ring of which iseither saturated, partially saturated or unsaturated, which may beoptionally benzofused if monocyclic or which may be optionallyspiro-fused, and wherein each Het consists of one or more carbon atomsand one boron atom and one or more oxygen atoms; one boron atom, oneoxygen atom, and one nitrogen atom; or one boron atom and one or morenitrogen atoms;

R⁵ is hydrogen, C₁₋₆alkyl, hydroxy, or —OR⁶;

R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl;

R⁷ is hydroxyalkyl, or aminoalkyl;

R⁸, R⁹, and R¹² are each independently hydroxy, alkoxy, or aminoalkyl;or R⁸ and R⁹ or R⁸, R⁹, and R¹² together with the boron atom to whichthey are attached form a 5 to 14-membered ring, said ring comprisingcarbon atoms and optionally one or more heteroatoms which can be N or O;said ring may be optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR¹³,C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyl each of which may beoptionally substituted with one or more substituents independentlyselected from the group consisting of hydroxy, amino, halogen, C(O)OH,C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹);

R¹⁰ and R¹¹ are each independently hydrogen or C₁₋₆alkyl;

R¹³ is alkoxy;

X is alkylene or —O-alkylene, wherein alkylene is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy,hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶,—S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰ and C₃₋₆cycloalkyl;

m is 1, 2, or 3;

or a pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue.

The present invention further provides a method of treatment ofHepatitis C Virus (HCV) in a human in need thereof comprisingadministering a compound of Formula (IIB):

wherein:

R is F or Cl;

R¹ is —C(O)NHR⁵;

R² is C₃₋₆cycloalkyl;

R³ is —S(O)₂R⁷;

R⁴ is

(a) heteroaryl substituted with B(R⁸)(R⁹) or XB(R⁸)(R⁹), and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl,hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵,—S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl;

(b) C₆₋₁₀aryl substituted with B(R⁸)(R⁹), or XB(R⁸)(R⁹), and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl,hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵,—S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to11-membered bicyclic heterocyclic ring system any ring of which iseither saturated, partially saturated or unsaturated, which may beoptionally benzofused if monocyclic or which may be optionallyspiro-fused, and wherein each Het consists of one or more carbon atomsand one boron atom and one or more oxygen atoms; one boron atom, oneoxygen atom, and one nitrogen atom; or one boron atom and one or morenitrogen atoms;

R⁵ is C₁₋₆alkyl;

R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl;

R⁷ is C₁₋₆alkyl, hydroxyalkyl, or aminoalkyl;

R⁸ and R⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R⁸and R⁹ together with the boron atom to which they are attached form a 5to 14-membered ring, said ring comprising carbon atoms and optionallyone or more heteroatoms which can be N or O; said ring may be optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, hydroxyalkyl, aminoalkyl, amino, oxo,C(O)OH, C(O)OXOR¹³, C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆ cycloalkyleach of which may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhydroxy, amino, halogen, C(O)OH, C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹);

R¹⁰ and R¹¹ are each independently hydrogen or C₁₋₆alkyl;

R¹³ is alkoxy;

X is alkylene or —O-alkylene, wherein alkylene is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy,hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶,—S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰ and C₃₋₆cycloalkyl; ora pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue.

Throughout this application, references are made to various embodimentsrelating to compounds, compositions, and methods. The variousembodiments described are meant to provide a variety of illustrativeexamples and should not be construed as descriptions of alternativespecies. Rather it should be noted that the descriptions of variousembodiments provided herein may be of overlapping scope. The embodimentsdiscussed herein are merely illustrative and are not meant to limit thescope of the present invention.

It is to be understood that the terminology used herein is for thepurpose of describing particular embodiments only and is not intended tolimit the scope of the present invention. In this specification and inthe claims that follow, reference will be made to a number of terms thatshall be defined to have the following meanings.

The term “alkyl” refers to a straight or branched hydrocarbon chaincontaining the specified number of carbon atoms. For example, C₁₋₆alkylmeans a straight or branched alkyl containing at least 1, and at most 6,carbon atoms. Examples of “alkyl” as used herein include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, and n-hexyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical, preferably having from one to sixcarbon atoms, unless specified otherwise. Examples of “alkylene” as usedherein include, but are not limited to, methylene, ethylene,n-propylene, n-butylene, and the like.

The term “alkoxy” refers to an alkyl radical containing the specifiednumber of carbon atoms attached through an oxygen linking atom. Forexample, C₁₋₆alkoxy refers to a straight- or branched-chain hydrocarbonradical having at least 1 and up to 6 carbon atoms attached through anoxygen linking atom. Examples of “alkoxy” as used herein include, butare not limited to, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy,but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.

The term “halogen” or “halo” refers to a fluorine (fluoro, F), chlorine(chloro, Cl), bromine (bromo, Br) or iodine (iodo, I) atom.

The terms “hydroxy” or “hydroxyl” refer to a radical or substituent ofthe formula OH.

The term “cycloalkyl” refers to a saturated cyclic group containing 3 to6 carbon ring-atoms (unless otherwise specified). Examples includecyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “aryl” refers to a carbocyclic aromatic moiety (such as phenylor naphthyl) containing the specified number of carbon atoms,particularly from 6-10 carbon atoms. Examples of aryl radicals include,but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl,anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyland the like. Unless otherwise indicated, the term “aryl” also includeseach possible positional isomer of an aromatic hydrocarbon radical, suchas in 1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl,6-tetrahydronaphthyl, 1-phenanthridinyl, 2-phenanthridinyl,3-phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl,8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl.

The term “heteroaryl” refers to a group or moiety comprising an aromaticmonovalent monocyclic or bicyclic radical, containing 5 to 10 ringatoms, including 1 to 4 heteroatoms independently selected fromnitrogen, oxygen and sulfur. This term also encompasses bicyclicheterocyclic-aryl compounds containing an aryl ring moiety fused to aheterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1to 4 heteroatoms independently selected from nitrogen, oxygen andsulfur. Illustrative examples of heteroaryls useful in the presentinvention include, but are not limited to, furanyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl,pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl,isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl,dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl,dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl,dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl,dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl,pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl,quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. All isomers ofthe above heteroaryl groups are within the scope of this invention. Eachheteroaryl group may be attached at any ring carbon or may be attachedthrough nitrogen when the nitrogen is part of a 5-membered ring.

Generally, the heteroaryl groups present in the compounds of thisinvention are 5-membered and/or 6-membered monocyclic heteroaryl groups.Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, orsulfur ring heteroatom, and optionally contain 1, 2, or 3 additionalnitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2,or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or6-membered heteroaryl groups useful in the present invention include,but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, and triazinyl.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen, such as N(O){N⁺—O⁻} and sulfur such as S(O)and S(O)₂, and the quaternized form of any basic nitrogen.

The term “heterocyclyl” refers to a 3- to 7-membered monocyclicheterocyclic ring which is saturated, partially saturated, orunsaturated. Each heterocyclyl consists of one or more carbon atoms andone or more oxygen, nitrogen, or sulfur atoms. The heterocyclyl may beattached at any carbon or nitrogen atom, provided that the attachmentresults in the creation of a stable structure. When the heterocyclyl hassubstituents, it is understood that the substituents may be attached toany atom in the ring, provided that a stable chemical structure results.Preferred heterocyclyl is imidazolyl.

The present invention provides a method for the treatment of Hepatitis CVirus (HCV) in a human in need thereof comprising administering acompound of Formula (II) or (IIB), or a pharmaceutically acceptable saltthereof, in combination with one or more of the following therapeuticagents: an HCV NS2 protease inhibitor, an HCV NS3/4A protease inhibitor,an HCV NS3 helicase inhibitor, an HCV NS4B replication factor inhibitor,an HCV NS5A replication factor inhibitor, an HCV NS5B polymeraseinhibitor, an HCV entry inhibitor, an HCV internal ribosome entry site(IRES) inhibitor, a microsomal triglyceride transfer protein (MTP)inhibitor, an α-glucosidase inhibitor, a caspase inhibitor, acyclophilin inhibitor, an immunomodulator, a metabolic pathwayinhibitor, an interferon, and a nucleoside analogue, which areadministered in effective amounts as is known in the art.

Examples of suitable HCV NS3/4A protease inhibitors include boceprevir(such as Victrelis™), telaprevir (such as Incivek™), simeprevir (alsoknown as TMC-435350), danoprevir (also known as RG7227 or ITMN-191),BI-201335, narlaprevir (also known as SCH 900518), vaniprevir (alsoknown as MK-7009), asunaprevir (also known as BMS-650032), GS 9256, GS9451, ACH-0141625, VX-985, ABT-450, PHX1766, IDX320, MK-5172, GNS-227,AVL-192, ACH-2684, and ACH-1095.

Examples of suitable HCV NS4B replication factor inhibitors includeclemizole.

Examples of suitable HCV NS5A replication factor inhibitors includeABT-267, BMS-790052, BMS-824393, BMS-766, AZD7295, CF102, GS 5885,PPI-461, PPM 301, PPI-437, PPI-668, PPI-833, ACH-2928, EDP-239, IDX380,and IDX719.

Examples of suitable HCV NS5B polymerase inhibitors include silibininsodium hemisuccinate, tegobuvir (also known as GS-9190), filibuvir (alsoknown as PF-00868554), VX-222, VX-759, ANA598, BMS-791325, ABT-333,ABT-072, BI 207127, IDX375, mericitabine (also known as RG7128), RG7348(also known as MB-11362), RG7432, PSI-7977, PSI-7851, PSI-352938,PSI-661, TMC 649128, IDX184, INX-08189, JTK-853, VCH-916, BILB 1941,GS-6620, and GS-9669.

Examples of suitable HCV entry inhibitors include PRO-206, ITX-5061,ITX4520, REP 9C, SP-30, and JTK-652.

Examples of suitable microsomal triglyceride transfer protein (MTP)inhibitors include BMS-201038 and CP-346086.

Examples of suitable α-glucosidase inhibitors include celgosovir (alsoknown as MX-3253 or MBI-3253) and castanospermine.

Examples of suitable caspase inhibitors include IDN-6556. Examples ofsuitable cyclophilin inhibitors include alisporivir (also known asDEBIO-025), NIM811 (also known as N-methyl-4-isoleucine cyclosporine),and SCY-635 (also known as[(R)-2-(N,N-dimethylamino)ethylthio-Sar]³-[4′-hydroxy-MeLeu]⁴-cyclosporinA).

Examples of suitable immunomodulators include Alloferon, IMN-6001,NOV-205, ME-3738, interleukin-7 (such as CYT 107), ANA-773, IMO-2125,and GS 9620.

Examples of suitable metabolic pathway inhibitors include ritonavir(such as Norvir®).

Examples of suitable interferons include interferon alfa-2a (such asRoferon-A®, Veldona®, or LBSI5535), peginterferon alfa-2a (such asPegasys®), interferon alfa-2b (such as Intron A® or Locteron®),peginterferon alfa-2b (such as PEG Intron® or P1101), interferon alfa-2banalogues (such as Hanferon™), interferon alpha-2b XL, interferonalfacon-1 (such as Infergen®), interferon alfa-n1 (such as Wellferon®),interferon omega (such as Biomed 510), HDV-interferon, peginterferonbeta (such as TRK-560), peginterferon lambda (such as BMS-914143), andinterferon-alpha5.

Examples of suitable nucleoside analogues include ribavirin (such asCopegus®, Ravanex®, Rebetol®, RibaPak™, Ribasphere®, Vilona®, andVirazole®), taribavirin (also known as viramidine), and isatoribine(also known as ANA245) and its prodrugs ANA971 and ANA975.

Additional examples, include, but are not limited to, ALS-2200,ALS-2158, PPI-383, PPI-393, PPI-461, PPI-668, and the antisense oligocalled mir-122.

When a compound of Formula (II) or (IIB), or a pharmaceuticallyacceptable salt thereof is used in combination with a second Hepatitistherapeutic agent the dose of each compound may differ from that whenthe compound is used alone. Appropriate doses will be readilyappreciated by those skilled in the art. It will be appreciated that theamount of a compound of the invention required for use in treatment willvary with the nature of the condition being treated and the age and thecondition of the patient and will be ultimately at the discretion of theattendant physician.

The individual components of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical compositions by any convenient route. When administrationis sequential, either the compound of Formula (II) or (IIB), or thesecond therapeutic agent may be administered first. When administrationis simultaneous, the combination may be administered either in the sameor different pharmaceutical composition.

The present invention further provides a pharmaceutical compositioncomprising a compound of Formula (II) or (IIB), or a pharmaceuticallyacceptable salt thereof, and a second therapeutic agent as describedabove. When combined in the same formulation it will be appreciated thatthe two compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

The present invention provides a composition comprising administering acompound of Formula (II):

wherein:

R is independently selected from the group consisting of halogen,C₁₋₆alkyl, alkoxy, —CN, —CF₃, —O—C₆₋₁₀aryl optionally substituted byhalogen, and —O-heteroaryl optionally substituted by halogen;

R¹ is —C(O)OH, —C(O)NHR⁵ or heterocyclyl;

R² is C₁₋₆alkyl, C₃₋₆cycloalkyl, —C(H)F₂, —CF₃, or —OR⁶;

R³ is —S(O)₂R⁷ or —C(O)R⁷;

R⁴ is

(a) heteroaryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, hydroxy, hydroxyalkyl, aminoalkyl,—C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶,—NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl;

(b) C₆₋₁₀aryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, hydroxy, hydroxyalkyl, aminoalkyl,—C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶,—NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH,—C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to11-membered bicyclic heterocyclic ring system any ring of which iseither saturated, partially saturated or unsaturated, which may beoptionally benzofused if monocyclic or which may be optionallyspiro-fused, and wherein each Het consists of one or more carbon atomsand one boron atom and one or more oxygen atoms; one boron atom, oneoxygen atom, and one nitrogen atom; or one boron atom and one or morenitrogen atoms;

R⁵ is hydrogen, C₁₋₆alkyl, hydroxy, or —OR⁶;

R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl;

R⁷ is C₁₋₆alkyl, hydroxyalkyl, or aminoalkyl;

R⁸, R⁹, and R¹² are each independently hydroxy, alkoxy, or aminoalkyl;or R⁸ and R⁹ or R⁸, R⁹, and R¹² together with the boron atom to whichthey are attached form a 5 to 14-membered ring, said ring comprisingcarbon atoms and optionally one or more heteroatoms which can be N or O;said ring may be optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR¹³,C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyl each of which may beoptionally substituted with one or more substituents independentlyselected from the group consisting of hydroxy, amino, halogen, C(O)OH,C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹);

R¹⁰ and R¹¹ are each independently hydrogen or C₁₋₆alkyl;

R¹³ is alkoxy;

X is alkylene or —O-alkylene, wherein alkylene is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy,hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶,—S(O)₂NH₂, —CN, —OCF₃, —NR¹⁰R¹¹, —NHC(O)R¹⁰ and C₃₋₆cycloalkyl;

m is 1, 2, or 3;

or a pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue.

The present invention further provides a composition comprising acompound of Formula (IIB):

wherein:

R is F or Cl;

R¹ is —C(O)NHR⁵;

R² is C₃₋₆cycloalkyl;

R³ is —S(O)₂R⁷;

R⁴ is

(a) heteroaryl substituted with B(R⁸)(R⁹) or XB(R⁸)(R⁹), and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl,hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵,—S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl;

(b) C₆₋₁₀aryl substituted with B(R⁸)(R⁹), or XB(R⁸)(R⁹), and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl,hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵,—S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to11-membered bicyclic heterocyclic ring system any ring of which iseither saturated, partially saturated or unsaturated, which may beoptionally benzofused if monocyclic or which may be optionallyspiro-fused, and wherein each Het consists of one or more carbon atomsand one boron atom and one or more oxygen atoms; one boron atom, oneoxygen atom, and one nitrogen atom; or one boron atom and one or morenitrogen atoms;

R⁵ is C₁₋₆alkyl;

R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl;

R⁷ is C₁₋₆alkyl, hydroxyalkyl, or aminoalkyl;

R⁸ and R⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R⁸and R⁹ together with the boron atom to which they are attached form a 5to 14-membered ring, said ring comprising carbon atoms and optionallyone or more heteroatoms which can be N or O; said ring may be optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, hydroxyalkyl, aminoalkyl, amino, oxo,C(O)OH, C(O)OXOR¹³, C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆ cycloalkyleach of which may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhydroxy, amino, halogen, C(O)OH, C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹);

R¹⁰ and R¹¹ are each independently hydrogen or C₁₋₆alkyl;

R¹³ is alkoxy;

X is alkylene or —O-alkylene, wherein alkylene is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy,hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶,—S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰ and C₃₋₆cycloalkyl; ora pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue.

The present invention further provides a pharmaceutical compositioncomprising a compound of Formula (II):

wherein:

R is independently selected from the group consisting of halogen,C₁₋₆alkyl, alkoxy, —CN, —CF₃, —O—C₆₋₁₀aryl optionally substituted byhalogen, and —O-heteroaryl optionally substituted by halogen;

R¹ is —C(O)OH, —C(O)NHR⁵ or heterocyclyl;

R² is C₁₋₆alkyl, C₃₋₆cycloalkyl, —C(H)F₂, —CF₃, or —OR⁶;

R³ is —S(O)₂R⁷ or —C(O)R⁷;

R⁴ is

(a) heteroaryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl;

(b) C₆₋₁₀aryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to11-membered bicyclic heterocyclic ring system any ring of which iseither saturated, partially saturated or unsaturated, which may beoptionally benzofused if monocyclic or which may be optionallyspiro-fused, and wherein each Het consists of one or more carbon atomsand one boron atom and one or more oxygen atoms; one boron atom, oneoxygen atom, and one nitrogen atom; or one boron atom and one or morenitrogen atoms;

R⁵ is hydrogen, C₁₋₆alkyl, hydroxy, or —OR⁶;

R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl;

R⁷ is C₁₋₆alkyl, hydroxyalkyl, or aminoalkyl;

R⁸, R⁹, and R¹² are each independently hydroxy, alkoxy, or aminoalkyl;or R⁸ and R⁹ or R⁸, R⁹, and R¹² together with the boron atom to whichthey are attached form a 5 to 14-membered ring, said ring comprisingcarbon atoms and optionally one or more heteroatoms which can be N or O;said ring may be optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR¹³,C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyl each of which may beoptionally substituted with one or more substituents independentlyselected from the group consisting of hydroxy, amino, halogen, C(O)OH,C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹);

R¹⁰ and R¹¹ are each independently hydrogen or C₁₋₆alkyl;

R¹³ is alkoxy;

X is alkylene or —O-alkylene, wherein alkylene is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy,hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶,—S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰ and C₃₋₆cycloalkyl;

m is 1, 2, or 3;

or a pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue, or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical compositioncomprising a compound of Formula (IIB):

wherein:

R is F or Cl;

R¹ is —C(O)NHR⁵;

R² is C₃₋₆cycloalkyl;

R³ is —S(O)₂R⁷;

R⁴ is

(a) heteroaryl substituted with B(R⁸)(R⁹) or XB(R⁸)(R⁹), and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl,hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵,—S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl;

(b) C₆₋₁₀aryl substituted with B(R⁸)(R⁹), or XB(R⁸)(R⁹), and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl,hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵,—S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to11-membered bicyclic heterocyclic ring system any ring of which iseither saturated, partially saturated or unsaturated, which may beoptionally benzofused if monocyclic or which may be optionallyspiro-fused, and wherein each Het consists of one or more carbon atomsand one boron atom and one or more oxygen atoms; one boron atom, oneoxygen atom, and one nitrogen atom; or one boron atom and one or morenitrogen atoms;

R⁵ is C₁₋₆alkyl;

R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl;

R⁷ is C₁₋₆alkyl, hydroxyalkyl, or aminoalkyl;

R⁸ and R⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R⁸and R⁹ together with the boron atom to which they are attached form a 5to 14-membered ring, said ring comprising carbon atoms and optionallyone or more heteroatoms which can be N or O; said ring may be optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆alkyl, hydroxyalkyl, aminoalkyl, amino, oxo,C(O)OH, C(O)OXOR¹³, C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyleach of which may be optionally substituted with one or moresubstituents independently selected from the group consisting ofhydroxy, amino, halogen, C(O)OH, C(O)N(R¹⁰)(R¹¹), and)N(R¹⁰)(R¹¹);

R¹⁰ and R¹¹ are each independently hydrogen or C₁₋₆alkyl;

R¹³ is alkoxy;

X is alkylene or —O-alkylene, wherein alkylene is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy,hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶,—S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰ and C₃₋₆cycloalkyl; ora pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue, or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier.

The present invention features a compound of formula (II) as describedabove wherein R is one or two halogen.

The present invention features a compound of formula (II) as describedabove wherein R¹ is —C(O)NHR⁵.

The present invention features a compound of formula (II) as describedabove wherein R² is C₃₋₆cycloalkyl.

The present invention features a compound of formula (II) as describedabove wherein R³ is —S(O)₂R⁷ wherein R⁷ is C₁₋₆alkyl.

The present invention features a compound of formula (II) as describedabove wherein R⁴ is C₆₋₁₀aryl substituted with B(R⁸)(R⁹), wherein R⁸ andR⁹ are both hydroxy, and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —CN, —C(H)F₂ and —CF₃.

The present invention features a compound of formula (II) as describedabove wherein R⁴ is heteroaryl substituted with B(R⁸)(R⁹), wherein R⁸and R⁹ are both hydroxy, and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —CN, —C(H)F₂ and —CF₃.

The present invention features a compound of formula (II) as describedabove wherein R⁵ is C₁₋₆alkyl.

The present invention features a compound of formula (II) as describedabove wherein R⁶ is C₁₋₆alkyl.

The present invention features a compound of formula (II) as describedabove wherein R⁷ is C₁₋₆alkyl.

The present invention features a compound of formula (II) as describedabove wherein m is 1.

The present invention features a compound of formula (II) as describedabove wherein X is alkylene.

The present invention features a compound of formula (II) wherein R ishalogen; m is 1; R¹ is —C(O)NHR⁵ wherein R⁵ is C₁₋₆alkyl; R² isC₃₋₆cycloalkyl; R³ is —S(O)₂R⁷ wherein R⁷ is C₁₋₆alkyl and R⁴ isC₆₋₁₀aryl substituted with B(R⁸)(R⁹) or X(R⁸)(R⁹), wherein R⁸ and R⁹ areboth hydroxy; and wherein C₆₋₁₀aryl is optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, —CN, —C(H)F₂ and —CF₃.

The present invention features a compound of formula (II) wherein R ishalogen; m is 1; R¹ is —C(O)NHR⁵ wherein R⁵ is C₁₋₆alkyl; R² isC₃₋₆cycloalkyl; R³ is —S(O)₂R⁷ wherein R⁷ is C₁₋₆alkyl and R⁴ isheteroaryl substituted with B(R⁸)(R⁹) or X(R⁸)(R⁹), wherein R⁸ and R⁹are both hydroxy and wherein heteroaryl is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, —CN, —C(H)F₂ and —CF₃.

The present invention features a compound of formula (II) wherein R ishalogen; m is 1; R¹ is —C(O)NHR⁵ wherein R⁵ is C₁₋₆alkyl; R² isC₃₋₆cycloalkyl; R³—S(O)₂R⁷ wherein R⁷ is C₁₋₆alkyl, and R⁴ is Hetsubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy —CN, and oxo.

The present invention features a compound of formula (II) wherein R ishalogen; m is 1; R¹ is —C(O)NHR⁵ wherein R⁵ is C₁₋₆alkyl; R² isC₃₋₆cycloalkyl; R³—S(O)₂R⁷ wherein R⁷ is C₁₋₆alkyl, and R⁴ is Hetsubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxyl, and —CN.

The present invention features a compound of formula (IIB) as describedabove, wherein R⁴ is Het optionally substituted one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl and aminoalkyl,

The present invention features a compound of formula (IIB) as describedabove, wherein R⁶ is C₁₋₆alkyl.

The present invention features a compound of formula (IIB) as describedabove, wherein R⁷ is C₁₋₆alkyl.

The present invention features a compound of formula (IIB) as describedabove, wherein R⁸ and R⁹ are each independently hydroxy.

The present invention features a compound of formula (IIB) as describedabove, wherein X is alkylene.

The present invention features a compound of formula (II) or (IIB)wherein R⁸ and R⁹ together with the boron atom to which they areattached form a 5 to 8-membered ring; said ring comprising carbon atomsand one or more oxygen atoms. Such 5 to 8-membered rings include thoseformed from pinanediol, pinacol, perfluoropinacol, ethylene glycol,diethylene glycol, catechol, 1,2,-cyclohexanediol, 1,3-propanediol,2,3,-butanediol, 1,2,-butanediol, 1,4-butanediol, glycerol anddiethanolamine.

The present invention also features a compound of Formula (II) selectedfrom the group consisting of:

-   (2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronic    acid;-   (2-Chloro-4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronic    acid;-   4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronic    acid;-   3-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronic    acid;-   4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronic    acid;-   4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorophenylboronic    acid;-   4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronic    acid;-   6-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)pyridin-3-ylboronic    acid;-   (4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronic    acid;-   (4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(trifluoromethyl)phenyl)boronic    acid;-   (4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2,6-difluorophenyl)boronic    acid;-   (2-cyano-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronic    acid-   6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylic    acid;-   (4-(N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-6-yl)methylsulfonamido)-2-chlorophenyl)boronic    acid;-   6-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;-   (4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(methylsulfonyl)phenyl)boronic    acid;-   1-(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)-4-methyl-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide;-   ((4-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronic    acid;-   ((2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronic    acid;-   5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;-   (4-(N-(2-(4-Chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-cyanophenyl)boronic    acid;-   5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide;-   (2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronic    acid;-   5-Cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;-   6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-4-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;-   (3-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronic    acid;-   6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;-   6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,    enantiomer 1;-   6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,    enantiomer 2;-   5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-6-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;    and pharmaceutically acceptable salts thereof.

Certain compounds of Formulas (II) or (IIB) may also exist instereoisomeric forms (e.g. they may contain one or more asymmetriccarbon atoms). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The invention also extends to conformationalisomers of compounds of Formulas (II) or (IIB) and any geometric (cisand/or trans) isomers of said compounds.

It is understood that compounds of Formulas (II) or (IIB) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

It will also be appreciated that compounds of the invention which existas polymorphs, and mixtures thereof, are within the scope of the presentinvention.

The present invention also features a compound of Formulas (II) or (IIB)or a pharmaceutically acceptable salt thereof. As used herein, the term“pharmaceutically acceptable salts” refers to salts that retain thedesired biological activity of the subject compound and exhibit minimalundesired toxicological effects. For a review on suitable salts seeBerge et al, J. Pharm. Sci., 1977, 66, 1-19. The term “pharmaceuticallyacceptable salts” includes both pharmaceutically acceptable acidaddition salts and pharmaceutically acceptable base addition salts.

In certain embodiments, compounds of Formula Formulas (II) or (IIB) maycontain an acidic functional group and may therefore be capable offorming pharmaceutically acceptable base addition salts by treatmentwith a suitable base. Pharmaceutically acceptable base salts includeammonium salts (for example ammonium or tetraalkylammonium), metalsalts, for example alkali-metal or alkaline-earth-metal salts (such ashydroxides, sodium, potassium, calcium or magnesium), organic amines(such as tris[also known as tromethamine ortris(hydroxymethyl)aminomethane], ethanolamine, diethylamine,triethanolamine, choline, isopropylamine, dicyclohexylamine orN-methyl-D-glucamine), cationic amino acids (such as arginine, lysine orhistidine) or bases for insoluble salts (such as procaine orbenzathine).

In certain embodiments, compounds according to Formulas (II) or (IIB)may contain a basic functional group and may therefore be capable offorming pharmaceutically acceptable acid addition salts by treatmentwith a suitable acid. A pharmaceutically acceptable acid addition saltmay be formed by reaction of a compound of Formulas (II) or (IIB) with asuitable strong inorganic acid (such as hydrobromic, hydrochloric,sulfuric, nitric, phosphoric or perchloric) or a suitable strong organicacid, for example, sulfonic acids [such as p-toluenesulfonic,benzenesulfonic, methanesulfonic, ethanesulfonic,2-hydroxyethanesulfonic, naphthalenesulfonic (e.g.2-naphthalenesulfonic)], carboxylic acids (such as acetic, propionic,fumaric, maleic, benzoic, salicylic or succinic), anionic amino acids(such as glutamaic or aspartic), hydroxyl acids (such as citric, lactic,tartaric or glycolic), fatty acids (such as caproic, caprylic, decanoic,oleic or stearic) or acids for insoluble salts (such as pamoic orresinic [e.g. polystyrene sulfonate]), optionally in a suitable solventsuch as an organic solvent, to give salt which is usually isolated forexample by crystallisation and filtration. In one embodiment, apharmaceutically acceptable acid addition salt of a compound of FormulaFormulas (II) or (IIB) is a salt of a strong acid, for example ahydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate,phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt.

It will be appreciated by those skilled in the art that organoboronicacids and/or their organoboronate esters may form “ate” complex additionsalts, such as organoborate complex addition salts, in the presence ofsuitable nucleophilic complexing reagents. Suitable nucleophiliccomplexing reagents include, but are not limited to alkali metalhydroxides, for example lithium hydroxide, sodium hydroxide or potassiumhydroxide, or fluoride. Examples of organoborate complex addition saltsand methods for their preparation will be readily apparent. For example,one such suitable organoborate complex addition salt is an alkali metaltrihydroxyorganoborate salt, such as a sodium trihydroxyorganoboratesalt. By way of illustration, sodium trihydroxyarylborate and sodiumtrihydroxyalkylborate complex addition salts and methods for theirpreparation are described in Cammidge, A. N. et al, Org. Lett., 2006, 8,4071-4074. Pharmaceutically acceptable “ate” complex addition salts asdescribed herein are also considered to be within the scope of thisinvention.

The present invention features suitable pharmaceutically acceptablesalts of the compounds of Formulas (II) or (IIB) including acid salts,for example sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium andtris(tromethamine-tris(hydroxymethyl)aminomethane) salts and the like,or mono- or di-basic salts with the appropriate acid for example organiccarboxylic acids such as acetic, lactic, tartaric, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids and inorganic acids such as hydrochloric, sulfuric, phosphoric andsulfamic acids and the like.

The present invention features pharmaceutically acceptable base additionsalts of a compound of Formulas (II) or (IIB) which are salts of astrong base, for example, sodium, lysine, ammonium,N-methyl-D-glucamine, potassium, choline, arginine (for exampleL-arginine) or magnesium. In a further aspect the salt is sodium,lysine, ammonium, N-methyl-D-glucamine, potassium, choline or arginine(for example L-arginine).

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of Formulas (II)or (IIB).

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compounds of Formulas (II) or(IIB) and solvates of the salts of the compounds of Formulas (II) or(IIB) are included within the scope of the present invention.

It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of Formulas (II) or (IIB), which maybe made prior to a final deprotection stage, may not possesspharmacological activity as such, but may, in certain instances, beadministered orally or parenterally and thereafter metabolised in thebody to form compounds defined in the first aspect which arepharmacologically active. Such derivatives may therefore be described as“prodrugs”. All protected derivatives and prodrugs of compounds definedin the first aspect are included within the scope of the invention.Examples of suitable pro-drugs for the compounds of the presentinvention are described in Drugs of Today, Volume 19, Number 9, 1983, pp499-538 and in Topics in Chemistry, Chapter 31, pp 306-316 and in“Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (thedisclosures in which documents are incorporated herein by reference). Itwill further be appreciated by those skilled in the art, that certainmoieties, known to those skilled in the art as “pro-moieties”, forexample as described by H. Bundgaard in “Design of Prodrugs” (thedisclosure in which document is incorporated herein by reference) may beplaced on appropriate functionalities when such functionalities arepresent within the compounds of Formulas (II) or (IIB). Suitableprodrugs for compounds of the invention include: esters, carbonateesters, hemi-esters, phosphate esters, nitro esters, sulfate esters,sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides,ethers, acetals ketals, boronic esters and boronic acid anhydrides.

The compounds Formulas (II) or (IIB) have been found to exhibitantiviral activity, specifically HCV inhibitory activity, and maytherefore useful in treating or preventing viral infections, such as HCVinfections, or diseases associated with such infections, particularlywhen administered in combination with one or more alternativetherapeutic agents. In vitro studies have been performed whichdemonstrate the usefulness of compounds described herein as antiviralagents when administered in combination with a second therapeutic agent.

The present invention provides a method for treating and/or preventingviral infections, such as HCV infections, or diseases associated withsuch infections which method comprises administering to a subject, forexample a human, in need thereof, a therapeutically effective amount ofa compound of Formulas (II) or (IIB) or a pharmaceutically acceptablesalt thereof and a second therapeutic agent selected from the groupconsisting of an HCV NS2 protease inhibitor, an HCV NS3/4A proteaseinhibitor, an HCV NS3 helicase inhibitor, an HCV NS4B replication factorinhibitor, an HCV NS5A replication factor inhibitor, an HCV NS5Bpolymerase inhibitor, an HCV entry inhibitor, an HCV internal ribosomeentry site inhibitor, a microsomal triglyceride transfer proteininhibitor, an α-glucosidase inhibitor, a caspase inhibitor, acyclophilin inhibitor, an immunomodulator, a metabolic pathwayinhibitor, an interferon, and a nucleoside analogue. Another embodimentof the present invention provides the above method further comprisingadministering a third therapeutic agent independently selected from thegroup consisting of an HCV NS2 protease inhibitor, an HCV NS3/4Aprotease inhibitor, an HCV NS3 helicase inhibitor, an HCV NS4Breplication factor inhibitor, an HCV NS5A replication factor inhibitor,an HCV NS5B polymerase inhibitor, an HCV entry inhibitor, an HCVinternal ribosome entry site inhibitor, a microsomal triglyceridetransfer protein inhibitor, an α-glucosidase inhibitor, a caspaseinhibitor, a cyclophilin inhibitor, an immunomodulator, a metabolicpathway inhibitor, an interferon, and a nucleoside analogue. Anotherembodiment of the present invention provides the above method furthercomprising administering a fourth therapeutic agent independentlyselected from the group consisting of an HCV NS2 protease inhibitor, anHCV NS3/4A protease inhibitor, an HCV NS3 helicase inhibitor, an HCVNS4B replication factor inhibitor, an HCV NS5A replication factorinhibitor, an HCV NS5B polymerase inhibitor, an HCV entry inhibitor, anHCV internal ribosome entry site inhibitor, a microsomal triglyceridetransfer protein inhibitor, an α-glucosidase inhibitor, a caspaseinhibitor, a cyclophilin inhibitor, an immunomodulator, a metabolicpathway inhibitor, an interferon, and a nucleoside analogue. Anotherembodiment of the present invention provides the above method furthercomprising administering a fifth therapeutic agent independentlyselected from the group consisting of an HCV NS2 protease inhibitor, anHCV NS3/4A protease inhibitor, an HCV NS3 helicase inhibitor, an HCVNS4B replication factor inhibitor, an HCV NS5A replication factorinhibitor, an HCV NS5B polymerase inhibitor, an HCV entry inhibitor, anHCV internal ribosome entry site inhibitor, a microsomal triglyceridetransfer protein inhibitor, an α-glucosidase inhibitor, a caspaseinhibitor, a cyclophilin inhibitor, an immunomodulator, a metabolicpathway inhibitor, an interferon, and a nucleoside analogue.

One embodiment of the present invention provides a method of treatmentof Hepatitis C Virus in a human in need thereof comprising administeringa therapeutically effective amount of a compound of Formulas (II) or(IIB) and an interferon. Another embodiment of the present inventionprovides a method of treatment of Hepatitis C Virus in a human in needthereof comprising administering a therapeutically effective amount of acompound of Formulas (II) or (IIB), an interferon, and a nucleosideanalogue. Another embodiment of the present invention provides a methodof treatment of Hepatitis C Virus in a human in need thereof comprisingadministering a therapeutically effective amount of a compound ofFormulas (II) or (IIB) and a metabolic pathway inhibitor. Anotherembodiment of the present invention provides a method of treatment ofHepatitis C Virus in a human in need thereof comprising administering atherapeutically effective amount of a compound of Formulas (II) or(IIB), a metabolic pathway inhibitor, an interferon, and a nucleosideanalogue. Another embodiment of the present invention provides a methodof treatment of Hepatitis C Virus in a human in need thereof comprisingadministering a therapeutically effective amount of a compound ofFormulas (II) or (IIB) and an HCV NS3/4A protease inhibitor. Anotherembodiment of the present invention provides a method of treatment ofHepatitis C Virus in a human in need thereof comprising administering atherapeutically effective amount of a compound of Formulas (II) or (IIB)and an HCV NS5A replication factor inhibitor. Another embodiment of thepresent invention provides a method of treatment of Hepatitis C Virus ina human in need thereof comprising administering a therapeuticallyeffective amount of a compound of Formulas (II) or (IIB), an HCV NS3/4Aprotease inhibitor, and an HCV NS5A replication factor inhibitor.Another embodiment of the present invention provides a method oftreatment of Hepatitis C Virus in a human in need thereof comprisingadministering a therapeutically effective amount of a compound ofFormulas (II) or (IIB), an HCV NS3/4A protease inhibitor, an interferon,and a nucleoside analogue. Another embodiment of the present inventionprovides a method of treatment of Hepatitis C Virus in a human in needthereof comprising administering a therapeutically effective amount of acompound of Formulas (II) or (IIB), a metabolic pathway inhibitor, anHCV NS3/4A protease inhibitor, an interferon, and a nucleoside analogue.Another embodiment of the present invention provides a method oftreatment of Hepatitis C Virus in a human in need thereof comprisingadministering a therapeutically effective amount of a compound ofFormula (I), an HCV NS5A replication factor inhibitor, an interferon,and a nucleoside analogue. Another embodiment of the present inventionprovides a method of treatment of Hepatitis C Virus in a human in needthereof comprising administering a therapeutically effective amount of acompound of Formulas (II) or (IIB), an HCV NS3/4A protease inhibitor, anHCV NS5A replication factor inhibitor, an interferon, and a nucleosideanalogue.

In a specific embodiment of the present invention, the interferon isselected from the group consisting of interferon alfa-2a, peginterferonalfa-2a, interferon alfa-2b, peginterferon alfa-2b, an interferonalfa-2b analogue, interferon alpha-2b XL, interferon alfacon-1,interferon alfa-n1, interferon omega, HDV-interferon, peginterferonbeta, peginterferon lambda, and interferon-alpha5. In another specificembodiment of the present invention, the interferon is selected from thegroup consisting of interferon alfa-2a, peginterferon alfa-2a,interferon alfa-2b, peginterferon alfa-2b, an interferon alfa-2banalogue, interferon alfacon-1, and interferon alfa n1.

In another specific embodiment of the present invention, the metabolicpathway inhibitor is ritonavir. In another specific embodiment of thepresent invention, the metabolic pathway inhibitor is ritonavir, whichis administered at a daily dose of 100 mg. In another specificembodiment of the present invention, the metabolic pathway inhibitor isritonavir, which is administered at a daily dose of 200 mg.

In another specific embodiment of the present invention, the nucleosideanalogue is ribavirin. In another specific embodiment of the presentinvention, the nucleoside analogue is ribavirin, which is administeredat a daily dose of 800 mg. In another specific embodiment of the presentinvention, the nucleoside analogue is ribavirin, which is administeredat a daily dose of 1000 mg. In another specific embodiment of thepresent invention, the nucleoside analogue is ribavirin, which isadministered at a daily dose of 1200 mg.

In another specific embodiment of the present invention, HCV NS3/4Aprotease inhibitor is selected from the group consisting of boceprevir,telaprevir, simeprevir, danoprevir, narlaprevir, vaniprevir, andasunaprevir. In another specific embodiment of the present invention,HCV NS3/4A protease inhibitor is selected from the group consisting ofboceprevir and telaprevir.

In another specific embodiment of the present invention, the compound ofFormula (I) is a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference herein to therapy or treatment mayinclude, but is not limited to prevention, retardation, prophylaxis, andcure of the disease. The present invention provides compounds andpharmaceutical compositions for the treatment and prevention of viralinfections, such as HCV infections, as well as diseases associated withviral infections in living hosts. It will further be appreciated thatreferences herein to treatment or prophylaxis of HCV infection includetreatment or prophylaxis of HCV-associated disease such as liverfibrosis, cirrhosis and hepatocellular carcinoma.

Within the context of the present invention, the terms describing theindications used herein are classified in the Merck Manual of Diagnosisand Therapy, 17^(th) Edition and/or the International Classification ofDiseases 10^(th) Edition (ICD-10). The various subtypes of the disordersmentioned herein are contemplated as part of the present invention.

The compounds of Formulas (II) or (IIB) may be made by the processesdescribed herein or by any method known to those skilled in the art.

The invention further provides pharmaceutical compositions comprising acompound of Formulas (II) or (IIB) (hereinafter compound A) and a secondtherapeutic agent selected from the group consisting of an HCV NS2protease inhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3helicase inhibitor, an HCV NS4B replication factor inhibitor, an HCVNS5A replication factor inhibitor, an HCV NS5B polymerase inhibitor, anHCV entry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue (hereinafter compound B), and one or morepharmaceutically acceptable carriers, diluents, or excipients.Optionally, such pharmaceutical compositions may further comprise one ormore additional therapeutic agent(s) independently selected from thegroup consisting of an HCV NS2 protease inhibitor, an HCV NS3/4Aprotease inhibitor, an HCV NS3 helicase inhibitor, an HCV NS4Breplication factor inhibitor, an HCV NS5A replication factor inhibitor,an HCV NS5B polymerase inhibitor, an HCV entry inhibitor, an HCVinternal ribosome entry site inhibitor, a microsomal triglyceridetransfer protein inhibitor, an α-glucosidase inhibitor, a caspaseinhibitor, a cyclophilin inhibitor, an immunomodulator, a metabolicpathway inhibitor, an interferon, and a nucleoside analogue (hereinaftercompound C, compound D, etc.). The carrier(s), diluent(s), orexcipient(s) must be acceptable in the sense of being compatible withthe other ingredients of the formulation, capable of pharmaceuticalformulation, and not deleterious to the recipient thereof. In accordancewith another aspect of the invention there is also provided a processfor the preparation of a pharmaceutical composition comprising admixinga Compound A and Compound B, with one or more pharmaceuticallyacceptable carriers, diluents, or excipients. Such elements of thepharmaceutical compositions utilized may be presented in separatepharmaceutical combinations or formulated together in one pharmaceuticalcomposition. Accordingly, the invention further provides a combinationof pharmaceutical compositions one of which includes Compound A and oneor more pharmaceutically acceptable carriers, diluents, or excipientsand a pharmaceutical composition containing Compound B and one or morepharmaceutically acceptable carriers, diluents, or excipients.Optionally, the combination of pharmaceutical compositions may furthercomprise one or more additional pharmaceutical compositions, one ofwhich includes Compound C and one or more pharmaceutically acceptablecarriers, diluents, or excipients and optionally another which includesCompound D and one or more pharmaceutically acceptable carriers,diluents, or excipients.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose. Asis known to those skilled in the art, the amount of active ingredientper dose will depend on the condition being treated, the route ofadministration and the age, weight and condition of the patient.Preferred unit dosage compositions are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.Furthermore, such pharmaceutical compositions may be prepared by any ofthe methods well known in the pharmacy art.

Compounds A, B, C, D, etc. may be administered by any appropriate route.Suitable routes include oral, rectal, nasal, topical (including buccaland sublingual), vaginal, and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal, and epidural). Itwill be appreciated that the preferred route may vary with, for example,the condition of the recipient of the combination. It will also beappreciated that each of the agents administered may be administered bythe same or different routes and that any combination of compounds (e.g.Compounds A and B; Compounds A and C; Compounds A, B, and C) may becompounded together in a pharmaceutical composition.

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing, and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. Lubricants used in these dosage forms includesodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride and the like. Disintegrators include,without limitation, starch, methyl cellulose, agar, bentonite, xanthangum and the like. A powder mixture is prepared by mixing the compound,suitably comminuted, with a diluent or base as described above, andoptionally, with a binder such as carboxymethylcellulose, an aliginate,gelatin, or polyvinyl pyrrolidone, a solution retardant such asparaffin, a resorption accelerator such as a quaternary salt and/or anabsorption agent such as bentonite, kaolin or dicalcium phosphate.Optional ingredients include other binders such as starch, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth or sodium alginate,polyethylene glycol, waxes and the like. The powder mixture can bewet-granulated with a binder such as syrup, starch paste, acadiamucilage or solutions of cellulosic or polymeric materials, and forcingthrough a screen. As an alternative to granulating, the powder mixturecan be run through the tablet machine and the result is imperfectlyformed slugs broken into granules. The granules can be lubricated toprevent sticking to the tablet-forming dies by means of the addition ofstearic acid, a stearate salt, talc or mineral oil. The lubricatedmixture is then compressed into tablets. The compounds of the presentinvention can also be combined with a free flowing inert carrier andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material, and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solution, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, compositions for oral administration can bemicroencapsulated. The composition can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The agents for use according to the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

Compounds A and B may be employed in combination in accordance with theinvention by administration simultaneously in a unitary pharmaceuticalcomposition including both compounds. Alternatively, the combination maybe administered separately in separate pharmaceutical compositions, eachincluding one of the compounds A and B in a sequential manner wherein,for example, Compound A or Compound B is administered first and theother second. Such sequential administration may be close in time (e.g.simultaneously) or remote in time. Furthermore, it does not matter ifthe compounds are administered in the same dosage form, e.g. onecompound may be administered parenterally and the other compound may beadministered orally. Suitably, both compounds are administered orally.Optionally, Compound C may be administered in combination with either orboth of Compounds A and B or may be administered separately in separatepharmaceutical composition. Compound C may be administeredsimultaneously with either or both of Compounds A and B or may beadministered in a sequential manner relative to either or both ofCompounds A and B. Optionally, Compound D may be administered incombination with any or all of Compounds A, B, and C or may beadministered separately in separate pharmaceutical composition. CompoundD may be administered simultaneously with any or all of Compounds A, B,and C or may be administered in a sequential manner relative to any orall of Compounds A, B, and C.

Thus, in one embodiment, one or more doses of Compound A areadministered simultaneously or separately with one or more doses ofCompound B. Unless otherwise defined, in all dosing protocols describedherein, the regimen of compounds administered does not have to commencewith the start of treatment and terminate with the end of treatment, itis only required that the number of consecutive days in which bothcompounds are administered and the optional number of consecutive daysin which only one of the component compounds is administered, or theindicated dosing protocol—including the amount of compound administered,occur at some point during the course of treatment.

In one embodiment, multiple doses of Compound A are administeredsimultaneously or separately with multiple doses of Compound B.

In another embodiment, multiple doses of Compound A are administeredsimultaneously or separately with one dose of Compound B.

In another embodiment, one dose of Compound A is administeredsimultaneously or separately with multiple doses of Compound B.

In another embodiment one dose of Compound A is administeredsimultaneously or separately with one dose of Compound B.

In all the above embodiments Compound A may be administered first orCompound B may be administered first.

The combinations may be presented as a combination kit. By the term“combination kit” or “kit of parts” as used herein is meant thepharmaceutical composition or compositions that are used to administerCompound A and Compound B according to the invention. Optionally, thekit may further comprise pharmaceutical composition or compositions thatare used to administer Compound C and optionally Compound D. WhenCompound A and Compound B are administered simultaneously, thecombination kit can contain Compound A and Compound B in a singlepharmaceutical composition, such as a tablet, or in separatepharmaceutical compositions. Optionally, the kit may contain CompoundsA, B, and C in a single pharmaceutical composition, such as a tablet, orany two of Compounds A, B, and C in a single pharmaceutical composition,or each of Compounds A, B, and C in a separate pharmaceuticalcomposition. Optionally, the kit may contain Compounds A, B, C, and D ina single pharmaceutical composition, such as a tablet, or any three ofCompounds A, B, C, and D in a single pharmaceutical composition, or anytwo of Compounds A, B, C, and D in a single pharmaceutical composition,or each of Compounds A, B, C, and D in a separate pharmaceuticalcomposition. When Compounds A and B are not administered simultaneously,the combination kit will contain Compound A and Compound B in separatepharmaceutical compositions either in a single package or Compound A andCompound B in separate pharmaceutical compositions in separate packages.Optionally, the kit may contain Compounds A, B, and C in separatepharmaceutical compositions either in a single package or in separatepackages. Optionally, the kit may contain Compounds A, B, C, and D inseparate pharmaceutical compositions either in a single package or inseparate packages.

In one embodiment of the invention there is provided a kit of partscomprising components:

Compound A in association with a pharmaceutically acceptable excipient,diluents, or carrier; and

Compound B in association with a pharmaceutically acceptable excipient,diluents, or carrier.

In another embodiment of the invention there is provided a kit of partscomprising components:

Compound A in association with a pharmaceutically acceptable excipient,diluents, or carrier; and

Compound B in association with a pharmaceutically acceptable excipient,diluents, or carrier, wherein the components are provided in a formwhich is suitable for sequential, separate, and/or simultaneousadministration.

In another embodiment of the invention there is provided a kit of partscomprising components:

a first container comprising Compound A in association with apharmaceutically acceptable excipient, diluents, or carrier; and

a second container comprising Compound B in association with apharmaceutically acceptable excipient, diluents, or carrier, and acontainer means for containing said first and second containers.

In another embodiment of the invention there is provided a kit of partscomprising components:

Compound A in association with a pharmaceutically acceptable excipient,diluents, or carrier;

Compound B in association with a pharmaceutically acceptable excipient,diluents, or carrier; and

Compound C in association with a pharmaceutically acceptable excipient,diluents, or carrier.

In another embodiment of the invention there is provided a kit of partscomprising components:

Compound A in association with a pharmaceutically acceptable excipient,diluents, or carrier;

Compound B in association with a pharmaceutically acceptable excipient,diluents, or carrier; and

Compound C in association with a pharmaceutically acceptable excipient,diluents, or carrier, wherein the components are provided in a formwhich is suitable for sequential, separate, and/or simultaneousadministration.

In another embodiment of the invention there is provided a kit of partscomprising components:

a first container comprising Compound A in association with apharmaceutically acceptable excipient, diluents, or carrier;

a second container comprising Compound B in association with apharmaceutically acceptable excipient, diluents, or carrier; and

a third container comprising Compound C in association with apharmaceutically acceptable excipient, diluents, or carrier, and acontainer means for containing said first, second, and third containers.

In another embodiment of the invention there is provided a kit of partscomprising components:

Compound A in association with a pharmaceutically acceptable excipient,diluents, or carrier;

Compound B in association with a pharmaceutically acceptable excipient,diluents, or carrier;

Compound C in association with a pharmaceutically acceptable excipient,diluents, or carrier; and

Compound D in association with a pharmaceutically acceptable excipient,diluents, or carrier.

In another embodiment of the invention there is provided a kit of partscomprising components:

Compound A in association with a pharmaceutically acceptable excipient,diluents, or carrier;

Compound B in association with a pharmaceutically acceptable excipient,diluents, or carrier;

Compound C in association with a pharmaceutically acceptable excipient,diluents, or carrier; and

Compound D in association with a pharmaceutically acceptable excipient,diluents, or carrier, wherein the components are provided in a formwhich is suitable for sequential, separate, and/or simultaneousadministration.

In another embodiment of the invention there is provided a kit of partscomprising components:

a first container comprising Compound A in association with apharmaceutically acceptable excipient, diluents, or carrier;

a second container comprising Compound B in association with apharmaceutically acceptable excipient, diluents, or carrier;

a third container comprising Compound C in association with apharmaceutically acceptable excipient, diluents, or carrier; and

a fourth container comprising Compound D in association with apharmaceutically acceptable excipient, diluents, or carrier, and acontainer means for containing said first, second, third, and fourthcontainers.

Suitably the combinations of this invention are administered within a“specified period”. By the term “specified period” as used herein ismeant the interval of time between the administration of, for example,one of Compound A and Compound B and the other of Compound A andCompound B. Unless otherwise defined, the specified period can includesimultaneous administration. When Compound A and Compound B areadministered once a day, the specified period refers to administrationof Compound A and Compound B during a single day. When one or bothcompounds are administered more than once a day, the specified period iscalculated based on the first administration of each compound on aspecific day. All administrations of a compound of the invention thatare subsequent to the first during a specific day are not consideredwhen calculating the specific period.

Suitably, if the compounds are administered within a “specified period”and not administered simultaneously, they are administered within about24 hours of each other—in this case, the specified period will be about24 hours; suitably they will be administered within about 12 hours ofeach other—in this case, the specified period will be about 12 hours;suitably they will be administered within about 11 hours of eachother—in this case, the specified period will be about 11 hours;suitably they will be administered within about 10 hours of eachother—in this case, the specified period will be about 10 hours;suitably they will be administered within about 9 hours of each other—inthis case, the specified period will be about 9 hours; suitably theywill be administered within about 8 hours of each other—in this case,the specified period will be about 8 hours; suitably they will beadministered within about 7 hours of each other—in this case, thespecified period will be about 7 hours; suitably they will beadministered within about 6 hours of each other—in this case, thespecified period will be about 6 hours; suitably they will beadministered within about 5 hours of each other—in this case, thespecified period will be about 5 hours; suitably they will beadministered within about 4 hours of each other—in this case, thespecified period will be about 4 hours; suitably they will beadministered within about 3 hours of each other—in this case, thespecified period will be about 3 hours; suitably they will beadministered within about 2 hours of each other—in this case, thespecified period will be about 2 hours; suitably they will beadministered within about 1 hour of each other—in this case, thespecified period will be about 1 hour. As used herein, theadministration of Compound A and Compound B in less than about 45minutes apart is considered simultaneous administration.

Suitably, when the combination of the invention is administered for a“specified period”, the compounds will be co-administered for a“duration of time”. By the term “duration of time” as used herein ismeant that each of the compounds of the invention are administered foran indicated number of consecutive days.

Regarding “specified period” administration: Suitably, each of thecompounds will be administered within a specified period for at leastone day—in this case, the duration of time will be at least one day;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 3 consecutivedays—in this case, the duration of time will be at least 3 days;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 5 consecutivedays—in this case, the duration of time will be at least 5 days;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 7 consecutivedays—in this case, the duration of time will be at least 7 days;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 14 consecutivedays—in this case, the duration of time will be at least 14 days;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 30 consecutivedays—in this case, the duration of time will be at least 30 days;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 60 consecutivedays—in this case, the duration of time will be at least 60 days;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 90 consecutivedays—in this case, the duration of time will be at least 90 days;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 180 consecutivedays—in this case, the duration of time will be at least 180 days;suitably, during the course of treatment, each of the compounds will beadministered within a specified period for at least 365 consecutivedays—in this case, the duration of time will be at least 365 days.

Further regarding “specified period” administration: Suitably, duringthe course of treatment, Compound A and Compound B will be administeredwithin a specified period for from 1 to 4 days over a 7 day period, andduring the other days of the 7 day period Compound A will beadministered alone or optionally with Compound C and optionally CompoundD. Suitably, this 7 day protocol is repeated for 2 cycles or for 14days; suitably for 4 cycles or 28 days; suitably for 12 cycles or 84days; suitably for continuous administration.

Suitably, during the course of treatment, Compound A and Compound B willbe administered within a specified period for 1 day during a 7 dayperiod, and during the other days of the 7 day period Compound A will beadministered alone or optionally with Compound C and optionally CompoundD. Suitably, this 7 day protocol is repeated for 2 cycles or for 14days; suitably for 4 cycles or 28 days; suitably for 12 cycles or 84days; suitably for continuous administration.

Suitably, if the compounds are not administered during a “specifiedperiod”, they are administered sequentially. By the term “sequentialadministration”, and derivates thereof, as used herein is meant that oneof Compound A and Compound B is administered for two or more consecutivedays and the other of Compound A and Compound B is subsequentlyadministered for two or more consecutive days. Also, contemplated hereinis a drug holiday utilized between the sequential administration of oneof Compound A and Compound B and the other of Compound A and Compound B.As used herein, a drug holiday is a period of days after the sequentialadministration of one of Compound A and Compound B and before theadministration of the other of Compound A and Compound B where neitherCompound A nor Compound B is administered. Suitably the drug holidaywill be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13days, and 14 days.

Regarding sequential administration: Suitably, one of Compound A andCompound B is administered for from 2 to 30 consecutive days, followedby an optional drug holiday, followed by administration of the other ofCompound A and Compound B for from 2 to 30 consecutive days. Suitably,one of Compound A and Compound B is administered for from 2 to 21consecutive days, followed by an optional drug holiday, followed byadministration of the other of Compound A and Compound B for from 2 to21 consecutive days. Suitably, one of Compound A and Compound B isadministered for from 2 to 14 consecutive days, followed by a drugholiday of from 1 to 14 days, followed by administration of the other ofCompound A and Compound B for from 2 to 14 consecutive days. Suitably,one of Compound A and Compound B is administered for from 3 to 7consecutive days, followed by a drug holiday of from 3 to 10 days,followed by administration of the other of Compound A and Compound B forfrom 3 to 7 consecutive days.

Suitably, Compound B will be administered first in the sequence,followed by an optional drug holiday, followed by administration ofCompound A. Suitably, Compound B is administered for from 2 to 21consecutive days, followed by an optional drug holiday, followed byadministration of Compound A for from 2 to 21 consecutive days.Suitably, Compound B is administered for from 3 to 21 consecutive days,followed by a drug holiday of from 1 to 14 days, followed byadministration of Compound A for from 3 to 21 consecutive days.Suitably, Compound B is administered for from 3 to 21 consecutive days,followed by a drug holiday of from 3 to 14 days, followed byadministration of Compound A for from 3 to 21 consecutive days.

Suitably, Compound A will be administered first in the sequence,followed by an optional drug holiday, followed by administration ofCompound B. Suitably, Compound A is administered for from 2 to 21consecutive days, followed by an optional drug holiday, followed byadministration of Compound B for from 2 to 21 consecutive days.Suitably, Compound A is administered for from 3 to 21 consecutive days,followed by a drug holiday of from 1 to 14 days, followed byadministration of Compound B for from 3 to 21 consecutive days.Suitably, Compound A is administered for from 3 to 21 consecutive days,followed by a drug holiday of from 3 to 14 days, followed byadministration of Compound B for from 3 to 21 consecutive days.

It is understood that a “specified period” administration and a“sequential” administration can be followed by repeat dosing or can befollowed by an alternate dosing protocol, and a drug holiday may precedethe repeat dosing or alternate dosing protocol.

Suitably, the amount of Compound A (based on weight ofunsalted/unsolvated amount) administered as part of the combinationaccording to the present invention will be in the range of 0.01 to 100mg per kilogram body weight of the recipient (e.g. a human) per day;suitably, the amount will be selected in the range of 0.1 to 30 mg perkilogram body weight per day; suitably, the amount will be selected inthe range of 0.1 to 10 mg per kilogram body weight per day; suitably,the amount will be selected in the range of 0.5 to 10 mg per kilogrambody weight per day. The desired dose may be presented as one, two,three, four, five, six or more sub-doses administered at appropriateintervals throughout the day. In some cases the desired dose may begiven on alternative days or other appropriate schedule, for example,weekly, or monthly. These sub-doses may be administered in unit dosageforms, for example, containing 0.5 to 100 mg, 5 to 1000 mg or 50 to 500mg, or 20 to 500 mg, of active ingredient per unit dosage form.

The following non-limiting examples illustrate the present invention.

EXAMPLES

It will be appreciated by those skilled in the art that when solventsare used in reactions it is desirable to use anhydrous solvents. It isfurther desirable to conduct reactions under an inert atmosphere, forexample under nitrogen or argon, where appropriate.

ABBREVIATIONS

-   -   μL=microliters    -   μM=micromolar    -   NMR=nuclear magnetic resonance    -   br=broad    -   d=doublet    -   δ=chemical shift    -   ° C.=degrees celcius    -   dd=doublet of doublets    -   DMEM=Dulbeco's Modified Eagle's Medium    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   g=gram    -   hr=hours    -   HCV=hepatitis C virus    -   HPLC=high performance liquid chromatography    -   Hz=hertz    -   J=coupling constant (given in Hz unless otherwise indicated)    -   m=multiplet    -   M=molar    -   M+H⁺=parent mass spectrum peak plus H⁺    -   mg=milligram    -   mL=milliliter    -   mM=millimolar    -   mmol=millimole    -   MS=mass spectrum    -   nM=nanomolar    -   ppm=parts per million    -   s=singlet    -   t=triplet

The compounds of the present invention may be prepared by one of skillin the art according to the synthetic examples and teachings foundwithin the following application: PCT Patent Application No.PCT/US2012/050268. which is incorporated herein in its entirety. Thecompounds of the present invention may also be prepared by one of skillin the art by following the synthetic examples below.

It will be appreciated by those skilled in the art that when solventsare used in reactions it is desirable to use anhydrous solvents. It isfurther desirable to conduct reactions under an inert atmosphere, forexample under nitrogen or argon, where appropriate.

The compounds of formula (II) and (IIB) may be prepared by the followingmethods or by any method known to one skilled in the art.

Compounds of formula (II) of type IX (R_(a)=halogen, R_(b) &R_(c)=halogen, alkyl, alkoxy, or ring) are readily prepared from thecorresponding bromide (III) compounds or corresponding triflate (IV,where P=OTf) compounds using conditions known to those skilled in theart. For example, conversion of III to the corresponding pinacolboronate can be accomplished by treatment with a catalyst (for examplePdCl₂(dppf)), base (for example KOAc), boron source (for examplebis-pinacol diboron) in solvent (for example 1,4-dioxane) with heat (forexample 80° C.). Subsequent treatment with an acid (for example HCl) insolvent mixture (for example THF/water) with a pinacol scavenger (forexample polymer-supported benzeneboronic acid) or with sodium periodateaffords IX. Further, those skilled in the art will recognize nitro IIcan be converted to the corresponding aniline using reduction conditionsincluding a catalyst (for example 10% palladium on carbon) in a solvent(for example THF) under an atmosphere of hydrogen. Subsequent use of aSandmeyer reaction, including an oxidant (for example sodium nitrite),an acid (for example HBr) and cuprous bromide in solvent (for exampleMeCN) affords III. The triflate (IV, where P=OTf) compounds can begenerated by treatment of the corresponding phenol intermediate IV(where P=H) with a triflating reagent (for example, triflic anhydride).

Compounds II, III and IV are readily available from coupling of thecorresponding sulfonamide V (where R_(a)=halogen) with either anitro-fluoroarene (VI) or bromo boronic acid (VII) or phenol-protectedboronic acid (VIII, where P=benzyl)). In the case of the former, directtreatment of V with a base (for example LiHMDS or potassium carbonate)in solvent (for example DMF) followed by exposure to VI gives thecorresponding SN_(AR) displacement products II. Additionally, treatmentof sulfonamide V with an aryl boronic acid such as VII or VIII (whereP=benzyl) using Chan-Lam coupling conditions, including a copper source(for example copper (II) acetate), a base (for example triethylamine),and a desiccant (for example 3 or 4 Å molecular sieves) in solvent (forexample DCM) affords the corresponding bromide III or phenol-protectedintermediate IV (where P=benzyl) which upon deprotection (for examplevia hydrogenation of the benzyl group) give the phenol intermediate IV(where P=H).

Bicyclic oxaboryl analogs such as X can be made in an analogous fashion.For example, coupling of the corresponding sulfonamide V (whereRa=halogen) with a nitro-fluoroarene VI in the presence of a base (forexample LiHMDS or potassium carbonate) in solvent (for example DMF)yields compounds such as XI. Nitro XI can be converted to thecorresponding aniline XII (where X=H) using reduction conditionsincluding a catalyst (for example 10% palladium on carbon) in a solvent(for example THF) under an atmosphere of hydrogen. The correspondinganiline XII can be converted to the bromide XIII (X=H) by those skilledin the art via a Sandmeyer reaction, wherein the aniline XII is treatedwith an oxidant (for example sodium nitrite), an acid (for example HBr)and cuprous bromide in solvent (for example MeCN). Alternatively, theaniline XII (where X=H) can be treated with an electrophilic halogensource (for example, N-chlorosuccinimide) in a solvent (for example,MeCN) to give the corresponding halogenated aniline XII (where X=Cl).The aniline can then be converted to the corresponding bromide XIII(where X=Cl) via the Sandmeyer reaction described previously. The esterfunctionality of intermediate XIII (where X=H or Cl) can be reduced tothe corresponding benzylic alcohol XIV (where P=H) by a number ofvarious reducing agents (for example, LiBH₄) in a solvent (for example,THF). Protection of the alcohol with any number of protecting groups(for example, -MOM) can be accomplished by those skilled in the art bytreatment of the benzylic alcohol XIV (where P=H) with a base (forexample, DIPEA) and a protecting group (for example, MOM-Cl) in asolvent (for example, THF) to give the MOM-protected benylic alcohol XIV(where P=MOM). The bromide can then be converted to the correspondingboronic ester by those skilled in the art. For example, conversion ofXIV (where P=MOM) to the corresponding pinacol boronate can beaccomplished by treatment with a catalyst (for example PdCl₂(dppf)),base (for example KOAc), boron source (for example bis-pinacol diboron)in solvent (for example 1,4-dioxane) with heat (for example 80° C.).Subsequent treatment with an acid (for example HCl) in solvent (forexample THF) removes both the pinacol ester and the MOM-protectinggroup, thereby forming the bicyclic oxaboryl analog X.

In a manner similar to that described above, compounds of type XV may beobtained directly by treatment of compounds of formula V with those ofXVI in the presence of a base (for example sodium hydride or LHMDS) insolvent (for example THF). Conversion of the resulting bromide tocompounds of formula XVI can be achieved in a manner analogous to theconversion of compound III to compound IX.

Boronic acids of type XVII are accessible via alkylation of thecorresponding phenol intermediate IV (where P=H) with2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in thepresence of a base (for example, K₂CO₃) and in a suitable solvent (forexample, DMF). Removal of the pinacol group with conditions describedherein yields the corresponding boronic acids XVII. Those skilled in theart will recognise that benzylic boronic acids of type XVIII areaccessible from the corresponding boronic esters of type IX or from thecorresponding bromides of type III. For example, treatment of theappropriately protected pinacol boronic ester IX with LiCH₂Cl in anappropriate solvent (for example, THF) at low temperature (for example,−78° C.) as described in the literature (for example, J. Med. Chem.2010, 53, 7852) yields the corresponding benzylic boronic ester XVIII(where R_(d)=H). Alternatively, the corresponding benzylic boronicesters of type XVIII (where R_(d)=H) can be prepared from theappropriately substituted aryl bromides of type III via halogen-metalexchange using a suitable alkyllithium (for example, tBuLi) in asuitable solvent (for example, THF) at low temperature (for example,−78° C.) followed by the addition of2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane).Alternatively, the corresponding benzylic boronic esters of type XVIIIcan be prepared from the appropriately substituted aryl bromides of typeIII via Pd-catalyzed cross-coupling of the aryl bromide with anappropriately substituted bis-boronic ester such XIX (where R_(d)=alkyl,benzyl) as described in the literature (for example, J. Am. Chem. Soc.2010, 132, 11033).

Cyclic oxaboryls of type XX (where R_(e)=H, alkyl) can be prepared viamultiple routes as described in the literature. For example, reaction ofbis-pinacol borane (B₂pin₂) to α,β-unsaturated esters (for example,where R_(f)=OMe), amides (for example, where R_(f)=NMe₂), and ketones(for example, where R_(f)=alkyl) of type XXII in the presence of a metalcatalyst (for example, CuCl or Rh(Phebox) XXIII) as described in theliterature (J. Org. Chem. 2011, 76, 3997 or Chem. Commun. 2009, 5987)yields intermediates of type XXI, which upon reduction of the ester,amide, or ketone and removal of the pinacol produce the correspondingcyclic oxaboryls XX (where R_(e)=H, alkyl).

The regioisomeric cyclic oxaboryls XXIV and XXV are readily prepared viahydroboration of the corresponding alkenes (XXVI and XXVII,respectively) by standard conditions described in the literature.

Intermediate Syntheses Intermediate 1:2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide

Step 1: Ethyl 3-(4-chlorophenyl)-3-oxopropanoate

To a solution of 4-chlorobenzoic acid (30.0 g, 0.192 mol) in DCM (250mL) was added oxalyl chloride (25 mL, 0.288 mol) and then DMF (0.5 mL)was added dropwise. The reaction mixture was refluxed for 2 hrs. Theresulting clear yellow solution was concentrated in vacuo to afford theacid chloride as yellow liquid. TEA (67 mL) was added to a solution ofethyl potassium malonate (41 g, 0.241 mol) in acetonitrile (537 mL).Upon cooling in an ice-salt bath, MgCl₂ (27.4 g, 0.288 mol) was addedand the resulting mixture was stirred at that temperature for 3 hrs. Theacid chloride (prepared as described above) was added and the reactionmixture was warmed to ambient temperature and stirred overnight. Themixture was cooled in an ice bath and 2N HCl (600 mL) was carefullyadded. The mixture was stirred in the ice bath for 1.5 hrs thentransferred to a separatory funnel and extracted with ethyl acetate(3×200 mL). The combined organic layers were washed with saturatedsodium bicarbonate (450 mL), brine (250 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to afford the crude productethyl 3-(4-chlorophenyl)-3-oxopropanoate (48.6 g) which was used withoutpurification.

Step 2: Ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate

Zinc chloride (28.3 g, 0.207 mol) was stirred in anhydrous ethanol (45mL) then heated to 95° C. (reflux) under nitrogen atmosphere using ovendried glassware. Ethyl 4-chlorobenzoylacetate (44 g, 0.194 mol) wasadded as a single portion followed by dropwise addition of a solution ofbenzoquinone (22.6 g, 0.21 mol) in anhydrous MTBE (500 mL) over 2 hours.This was performed with a simultaneous distillation of MTBE from thereaction mixture such that the reaction volume remained approximatelyconstant. A bath temperature of 145-155° C. and an internal temperatureof 75-95° C. maintained throughout most of the addition. Halfway throughthe addition more anhydrous ethanol (45 mL) was added because thereaction mixture became thick and a loss of some of the original volumeof ethanol through the distillation was suspected. After addition wascomplete, heating continued for 30 minutes. The reaction mixture wascooled to room temperature and partitioned between water (100 mL) andEtOAc (250 mL). The insoluble solids were removed by filtration of thebiphasic solution and the organic layer was then separated, washed withmore water, dried and evaporated under vacuum. The residual brown solidwas slurried in warm dichloromethane and the mixture cooled to roomtemperature and cooled further by refrigeration overnight. The tan solidwas filtered from the dark brown solution and washed with a small volumeof DCM and dried under vacuum to give ethyl2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate (27 g, 44%).

Step 3: Ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate

Ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate (26 g, 0.051mol) in NMP (160 mL) was added isopropyl bromide (15 mL), then cesiumcarbonate (33 g, 0.101 mol) was added. The reaction mixture was stirredin a 60° C. oil bath for 20 hrs then cooled to ambient temperature. Thereaction mixture was treated with 5% ammonium solution and stirred for15 min. This mixture was then diluted with water and extracted withhexane. The organic layer was washed with water, dried with anhydroussodium sulfate, filtered, and concentrated under reduced pressure togive ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate (15g, 82%).

Step 4: Ethyl2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate 4 (30 g,0.084 mol) was dissolved in chloroform (75 mL) and the resultingsolution was cooled in an ice bath. Nitric acid (55 mL) was alsodissolved in chloroform (75 mL) and cooled in an ice bath. The acidsolution was added dropwise to the solution of ethyl2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate over 1 hour, andthe reaction mixture was then stirred at 0° C. for 1.5 hrs. The reactionmixture was then diluted with water (60 mL) and the layers wereseparated. The organic layer was dried with anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to give a brown oilwhich was purified by column chromatography (5/1 PE/EA) to afford ethyl2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as abrown solid (11 g, 32%).

Step 5: Ethyl2-(4-chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate

Ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate(11 g, 27.2 mmol) was dissolved in anhydrous DCM (150 mL) and cooled inan ice bath under an atmosphere of nitrogen. Boron trichloride (41 mL,41.0 mmol) was added over ˜20 minutes. After the reaction was complete,the reaction mixture was quenched by pouring into an ice/water mixture.The mixture was extracted with DCM, and the combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum to give ethyl2-(4-chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (10.2 g,84%).

Step 6:Ethyl-2-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate

To a solution of ethyl2-(4-chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (10.2 g,22.9 mmol) and DMAP (0.289 g, 2.3 mmol) in anhydrous DCM (300 mL) andanhydrous TEA (4.8 mL) in an ice bath under nitrogen was addedtrifluoromethane sulfonic anhydride (5.62 mL, 34 mmol). The reactionmixture was stirred under nitrogen at 0° C. for 30 min then quenched at0° C. with water (200 mL) and extracted with DCM (3×200 mL). Thecombined organic layers were washed with water (3×600 mL), 2N HCl (2×300mL), water (300 mL), dried with anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford ethyl2-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate(10 g, 80%) as a yellow solid that was used without furtherpurification.

Step 7: Ethyl2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate

A mixture of2-(4-chlorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate(10 g, 18 mmol), KF (4.64 g, 79.9 mmol), NaBr (2.48 g, 24 mmol),cyclopropylboronic acid (3.2 g, 37 mmol), and Pd(Ph₃P)₄ (1.33 g, 1.15mmol) were added toluene (130 mL) and water (2.8 mL). The reaction flaskwas evacuated for ˜3 minutes then filled with nitrogen. The reactionmixture was refluxed under nitrogen for 20 hrs then cooled to ambienttemperature. The reaction mixture was diluted with EtOAc (150 mL),washed with water (3×200 mL), brine (200 mL), dried with anhydroussodium sulfate, decanted, and concentrated under reduced pressure. Theresidue was purified by column chromatography (petroleum ether/ethylacetate=30/1-10/1) to afford ethyl2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate as ayellow solid (7.9 g, 99%).

Step 8: Ethyl6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate

To a solution of ethyl2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate (8 g,18.2 mmol) in ethyl acetate (450 mL) was added 10% palladium oncarbonate (1.83 g), 1N HCl solution (2.5 mL), and stirred with under 0.4MPa of hydrogen at room temperature for 8 hrs. The reaction mixture wasfiltered through celite and the filtrate was evaporated under vacuum togive ethyl6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate as abrown solid (7.4 g, 99%).

Step 9: Ethyl2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate

To a solution of ethyl6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (7.4 g,18.06 mmol) in dry dichloromethane (170 mL) at −15° C. under N₂atmosphere was added dry TEA (6.73 mL, 45.15 mmol) and thenmethanesulfonyl chloride (4.91 mL, 63.2 mmol) dropwise. The stirredsolution was warmed to room temperature and stirred for 2 hours. Thereaction mixture was diluted with water (100 mL) and extracted with DCM(3×150 mL). The organic layers were combined, dried with Na₂SO₄,filtered and evaporated under vacuum to afford ethyl2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate(9.2 g, 99%).

Step 10:5-Cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylicacid

Potassium hydroxide (15.1 g, 270 mmol) was added to a solution of theethyl2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylatein ethanol (64 mL) and water (32 mL) under nitrogen atmosphere. Thereaction was refluxed for 1 hour and then concentrated in vacuo. Theremaining solid was dissolved in water and the solution was acidifiedwith 1N HCl (250 mL) until a precipitate formed. The solid was filteredand then dried to afford5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylicacid (8.7 g, quantitative yield).

Step 11:2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide

To a solution of5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylicacid (5 g, 11.52 mmol) in dry DMF (30 mL) was added DIPEA (3.3 g, 25.34mmol) and HATU (5.15 g, 13.5 mmol) at 20° C. After 15 minutes, 2MMethylamine in THF (23.04 mL, 46.08 mmol) was added dropwise and themixture was stirred for another 2 hours before water (60 mL) was added.The mixture was extracted with EA (3×200 mL), washed with water (2×200mL), dried and concentrated to afford2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamideas a brown solid (4.7 g, 97%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.32 (br.s., 1H) 8.45 (q, 1H) 7.90 (d, 2H) 7.53-7.64 (m, 3H) 7.16 (s, 1H) 3.06(s, 3H) 2.83 (d, 3H) 2.21-2.37 (m, 1H) 0.94-1.05 (m, 2H) 0.64-0.73 (m,2H). LCMS (m/z, ES⁺)=419 (M+H+).

Intermediate 2:5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide

Step 1: Methyl 2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate

Using oven dried glassware and under an atmosphere of nitrogen,anhydrous zinc chloride (25 g, 183 mmol) was stirred in anhydrousmethanol (60 mL) then heated to a 75° C. internal temperature. Methyl4-fluorobenzoylacetate (39.6 g, 202 mmol) was added as a single portionfollowed by dropwise addition of a solution of p-benzoquinone (19.83 g,183 mmol) in anhydrous diethyl ether (500 mL) over 4 hours. This wasperformed with a simultaneous distillation of ether from the reactionmixture such that the reaction volume remained approximately constant (abath temperature of 140° C. maintained an internal temperature initiallyat 75° C. then gradually increasing to a maximum of 115° C.). 2.5 hoursafter the start of the benzoquinone addition, more methanol (20 mL) wasadded to facilitate stirring. After addition of benzoquinone wascomplete, heating of the reaction mixture at 100° C. (internal)continued for 1 hour. The reaction mixture was cooled to roomtemperature and partitioned between water (500 mL) and ethyl acetate(800 mL). The insoluble solids were removed from the biphasic solutionby filtration and the organic layer was then separated, dried (Na₂SO₄),filtered and evaporated under vacuum. The brown residue was slurried inwarm dichloromethane (˜225 mL) and the mixture was left to stand in arefrigerator for 18 hours. The resulting solids were filtered from thedark brown solution, washed with a small volume of dichloromethane thendried under vacuum to give Methyl2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate. LCMS (m/z,ES⁺)=285 (M−1).

Step 2: Methyl2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate

A mixture of methyl2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate (18.86 g, 65.9mmol), isopropyl bromide (24.74 mL, 264 mmol) and cesium carbonate (42.9g, 132 mmol) in dry N-Methyl-2-pyrrolidone (191 mL) was stirred at 60°C. under nitrogen for 20 hours. The resultant thick suspension wasallowed to cool to room temperature and then 7% aqueous ammonia solution(200 mL) was added with rapid stirring. This mixture was extracted withheptane (700 mL) and then the aqueous phase was separated off. Ethylacetate (˜100 mL) was added to the organic phase and the resultantmixture was shaken and then dried over Na₂SO₄ and evaporated to give abrown oil which crystallized on standing overnight. This material wasrecrystallized from hot methanol and the solid was collected byfiltration, washed with methanol and finally dried under vacuum to givemethyl2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate.LCMS (m/z, ES⁺)=329 (M+1). The mother liquors from the firstrecrystallization were crystallized a second time to give an additionalbatch of methyl2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate.

Step 3: Methyl2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-6-nitro-1-benzofuran-3-carboxylate

To a solution of methyl2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate(6.16 g, 18.76 mmol) in chloroform (22 mL) at −15° C. was added dropwisea cold solution of 70% nitric acid (11 mL, 172 mmol) in chloroform (22mL). After stirring at 0° C. for 1 hour, the reaction mixture was washedwith water (50 mL) and the organic phase was separated by hydrophobicfilter tube then evaporated under vacuum to afford a brown solid. Thesolid was triturated in methyl tert-butyl ether (25 mL) and theresulting pale yellow powder was filtered off, washed with heptane anddried under vacuum to give methyl2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-6-nitro-1-benzofuran-3-carboxylate.LCMS (m/z, ES⁺)=764 (2M+NH₄).

Step 4: Methyl2-(4-fluorophenyl)-5-hydroxy-6-nitro-1-benzofuran-3-carboxylate

To a stirred solution of methyl2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-6-nitro-1-benzofuran-3-carboxylate(5.237 g, 14.03 mmol) in dry dichloromethane (70 mL) at −15° C., underan atmosphere of nitrogen, was added a 1M solution of boron trichloridein dichloromethane (23.85 mL, 23.85 mmol) over 30 minutes using asyringe pump. The dark brown-red reaction mixture was poured over ice(˜250 mL). The ice was allowed to melt and the mixture extracted withdichloromethane (˜450 mL). The organic phase was separated byhydrophobic filter tube and evaporated under vacuum to give the methyl2-(4-fluorophenyl)-5-hydroxy-6-nitro-1-benzofuran-3-carboxylate. ¹H NMR(d₆-DMSO): δ 10.97 (1H, br. s), 8.34 (1H, s), 8.07 (2H, dd), 7.67 (1H,s), 7.43 (2H, t), 3.86 (3H, s).

Step 5: Methyl2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylate

To an ice-cooled stirred mixture of methyl2-(4-fluorophenyl)-5-hydroxy-6-nitro-1-benzofuran-3-carboxylate (4.915g, 14.84 mmol) and 4-(dimethylamino)pyridine (0.181 g, 1.484 mmol) inanhydrous dichloromethane (130 mL) under nitrogen, was addedtriethylamine (3.10 mL, 22.26 mmol) followed by trifluoromethanesulfonicanhydride (3.76 mL, 22.26 mmol). After 50 minutes at 0° C., water wasadded and the organic layer was separated. The aqueous phase wasextracted with more dichloromethane and the combined organics werewashed with 2M HCl and water. The organics were dried by hydrophobicfilter tube and evaporated to give the Methyl2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylate.LCMS (m/z, ES⁺)=481 (M+NH₄)⁺.

Step 6: Methyl5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran-3-carboxylate

Methyl2-(4-fluorophenyl)-6-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}-1-benzofuran-3-carboxylate(7.12 g, 15.37 mmol), cyclopropylboronic acid (2.19 g, 25.5 mmol),potassium fluoride (3.26 g, 56.1 mmol), sodium bromide (1.75 g, 17.01mmol) and tetrakis(triphenylphosphine)palladium(0) (0.85 g, 0.736 mmol)were stirred together under nitrogen in a mixture of toluene (90 mL) andwater (2.25 mL) and heated at 100° C. for 18 hours. The reaction mixturewas cooled, diluted with ethyl acetate and washed with water. Theorganic phase was separated, dried by hydrophobic filter tube andevaporated under vacuum. The residue was purified by flashchromatography, eluting over silica gel with a gradient of 0-5% ethylacetate in cyclohexane. Product containing fractions were evaporatedunder vacuum to give the methyl5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran-3-carboxylate.LCMS (m/z, ES⁺)=728 (2M+NH₄)⁺.

Step 7: Methyl6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate

A solution of methyl5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran-3-carboxylate(3.175 g, 8.94 mmol) in ethyl acetate (250 mL) containing 2M HCl (17drops) was stirred with 10% palladium on carbon (0.951 g, 0.894 mmol)under an atmosphere of hydrogen at 21° C. for 16 hours. The reactionmixture was filtered through celite and the filtrate was evaporatedunder vacuum to give a dark green solid. This was dissolved indichloromethane, washed with sodium bicarbonate solution, separated byhydrophobic frit, then evaporated to dryness and purified by flashchromatography, eluting over silica gel with a gradient of 0-30% ethylacetate in cyclohexane. Appropriate fractions were combined andevaporated under vacuum to give the methyl6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate.LCMS (m/z, ES⁺)=326 (M+H+).

Step 8: Methyl6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate

A solution of methyl6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate(1.96 g, 6.02 mmol) and triethylamine (2.52 mL, 18.07 mmol) in drydichloromethane (40 mL) was cooled (ice bath) to 0° C., then treatedwith methanesulfonyl chloride (1.174 mL, 15.06 mmol). The reaction wasstirred at 0° C. (ice bath) for 2 hours. Water (100 mL) was added andthe organics extracted 3 times with dichloromethane, dried using anhydrophobic frit and evaporated to dryness to give the methyl6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate.LCMS (m/z, ES⁺)=482 (M+H+).

Step 9:5-Cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxylicacid

A suspension of methyl6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate(2.88 g, 5.98 mmol) in ethanol (50 mL) and water (25 mL) was treatedwith potassium hydroxide (6.71 g, 120 mmol) and heated at reflux for 1hour (the suspension went into solution upon heating). The reaction wasconcentrated under vacuum, water (100 mL) was added and the solutionacidified with 2M HCl (50 mL). The resulting precipitate was filtered,washed with 0.5 M HCl, then dissolved in methanol. This solution wasevaporated to dryness and azeotroped twice with toluene to give5-Cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxylicacid. LCMS (m/z, ES⁺)=390 (M+H+).

Step 10:5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide

A solution of5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxylicacid (2.52 g, 6.47 mmol), HATU (2.95 g, 7.77 mmol) and triethylamine(1.984 mL, 14.24 mmol) in dry dichloromethane (100 mL) was stirred atroom temperature for 1 hour, then treated with methylamine (16.18 mL,32.4 mmol). The solution was stirred at room temperature under nitrogenfor 4 hours, during which time a precipitate formed. The reaction wasdiluted with dichloromethane (300 mL) and sodium bicarbonate solution(200 mL) and stirred for 10 minutes. The layers were separated and theaqueous layer extracted with further dichloromethane (150 mL). Thecombined organics were washed with brine (200 mL), dried using ahydrophobic frit and evaporated to dryness to give an off-white solid.The crude product was purified by flash chromatography (eluting with0-100% ethyl acetate/cyclohexane followed by 10%methanol/dichloromethane) to give a white solid. The solid was dissolvedin hot methanol-chloroform (10% v/v), preabsorped onto silica gel andpurified by flash chromatography (0-10% methanol/dichloromethane) togive the5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (br s, 1H) 8.42 (q, 1H) 7.88-7.98(m, 2H) 7.60 (s, 1H) 7.37 (t, 2H) 7.16 (s, 1H) 3.06 (s, 3H) 2.83 (d, 3H)2.23-2.36 (m, 1H) 0.93-1.05 (m, 2H) 0.65-0.74 (m, 2H). LCMS (m/z,ES⁺)=403 (M+H+).

Example 1(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid

Step 1:6-(N-(3-Chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(12.5 g, 31.1 mmol), 2-chloro-4-fluoronitrobenzene (10.9 g, 62.1 mmol)and potassium carbonate (12.9 g, 93.0 mmol) in 130 mL of 4:1 DME/waterin a sealed flask was heated to 100° C. with stirring. An identical 12.5g scale reaction was set up in a second sealed vessel. The reactionvessels were maintained at 100° C. for 70 hours, cooled to RT, andstirred for an additional 18 hours. The combined reaction mixtures werepartitioned between EtOAc (300 mL) and water (600 mL), and the phasesseparated. The aqueous solution was extracted with two additional 150 mLportions of EtOAc. The combined EtOAc solutions were washed with halfsaturated brine (1×), saturated brine (1×), dried over sodium sulfateand concentrated to dryness at reduced pressure. The resultingyellow-brown solid was recrystallized from EtOAc/ether to give the titlecompound (22.3 g, 64%) as an off-white solid. LCMS (m/z, ES⁺)=558(M+H+).

Step 2:6-(N-(4-Amino-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(11.0 g, 19.7 mmol) in 1:1 THF/MeOH (75 mL) was subjected tohydrogenation at 40 psi in the presence of 5% sulfided platinum oncarbon (0.560 g). After 4 hours an additional portion of catalyst wasadded (0.250 g). After another 16 hours the reaction vessel was purgedwith nitrogen, catalyst removed by filtration through celite, and thefiltrate concentrated to dryness at reduced pressure. The residue wasrecrystallized from hexane/EtOAc to afford the title compound (10.3 g,99%) as a white solid. LCMS (m/z, ES⁺)=528 (M+H+).

Step 3:6-(N-(4-Bromo-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 1 L 3-necked flask equipped with a mechanical stirrer was added6-(N-(4-amino-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(10.0 g, 18.9 mmol) followed by acetonitrile (200 mL) and then 48%aqueous HBr (200 mL). A thick, lumpy suspension resulted which wasstirred vigorously for 30 minutes to afford a more uniform suspension.The reaction vessel was cooled in an ice water bath for 30 minutes andthe mixture treated with a solution of sodium nitrite (1.96 g, 28.4mmol) in water (20 mL) via addition funnel over 5 minutes. The resultingyellow suspension was stirred in the ice bath for 1.5 hours and thentreated with CuBr (4.1 g, 28.4 mmol) in small portions over 5 minutes.This afforded a dark brown solution that was warmed to 60° C. (internaltemperature) with continued stirring. After 40 minutes at elevatedtemperature the mixture was cooled to RT and poured into a rapidlystirred mixture of 5% aqueous sodium bisulfite (600 mL) and EtOAc (800mL). The phases were separated and the aqueous solution extracted withtwo additional 150 mL portions of EtOAc. The combined EtOAc solutionswere washed with 5% aqueous sodium bisulfite (2×150 mL), saturatedaqueous sodium bicarbonate (2×300 mL), saturated brine (1×200 mL), driedover sodium sulfate and concentrated to dryness at reduced pressure togive a yellow foam. This material was subjected to flash chromatography(silica gel, gradient from 9:1 hexane/EtOAc to EtOAc). Duringconcentration of the pure fractions a white solid crystallized out.After concentrating down to a thick suspension the mixture was dilutedwith 150 mL of hexane and the mixture stirred at RT overnight. The solidwas collected by filtration in a medium fritted funnel and dried invacuo to afford the title compound (8.55 g, 76%) as a white crystallinesolid. LCMS (m/z, ES⁺)=591,593 (M+H+).

Step 4:(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid

To a 350 mL screw capped flask equipped with a magnetic stirrer wasadded6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(8.54 g, 14.4 mmol), bis(pinacolato)diboron (18.3 g, 72.1 mmol),potassium acetate (7.08 g, 72.1 mmol), Pd(11)(dppf)Cl₂ dichloromethanecomplex (0.589 g, 0.721 mmol) and anhydrous 1,4-dioxane (150 mL). Themixture was sparged with nitrogen for 10 minutes. The vessel was sealedand heated in an 80° C. oil bath with stirring. After 4 hours themixture was cooled to RT and diluted with EtOAc (400 mL). The resultingblack solution was washed with water (2×), saturated brine (1×), anddried over sodium sulfate. While stirring with sodium sulfate, celitewas added to facilitate removal of the insoluble black material thatremained suspended in solution. The mixture was filtered through amedium frit to afford a golden-brown filtrate that was concentrated todryness at reduced pressure. The residue was dissolved in 300 mL of THFand the resulting solution cooled in an ice water bath. The solution wastreated with 1N aqueous HCl (120 mL) followed by sodium periodate (46.3g, 216 mmol). The mixture was stirred at 0° C. for 10 minutes and thenallowed to warm to RT. After 18 hours the mixture was partitionedbetween water and EtOAc and the phases separated. The aqueous solutionwas extracted with EtOAc (2×). The combined EtOAc solutions were washedwith 5% aqueous sodium bisulfite (4×), saturated brine (2×), dried oversodium sulfate and concentrated to dryness at reduced pressure. Theresidue was subjected to flash chromatography (silica gel, 2-partgradient: DCM to EtOAc over 15 minutes, then switch solvents to A=9:1DCM/MeOH, B=DCM; gradient from 100% B to 65% A over 4 minutes, then 65%A isocratic for 15 minutes) to give a light tan foam (7.28 g). Thismaterial was dissolved in acetonitrile (75 mL) and the solution stirredwith rapid dropwise addition of 0.25 N aqueous HCl (175 mL) over a 20minute period. A white suspension was produced which was stirred at RT.After 2 hours the solid was collected by filtration in a medium frittedfunnel. The filter cake was washed with water (2×), suction air driedfor 30 minutes, and then dried in vacuo overnight to afford the titlecompound (5.90 g, 74%) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δppm 7.90-7.97 (m, 2H) 7.85 (s, 1H) 7.29-7.41 (m, 4H) 7.26 (t, 2H) 3.34(s, 3H) 2.95 (s, 3H) 2.07-2.17 (m, 1H) 0.69-1.08 (m, 3H) 0.49 (br s,1H). LCMS (m/z, ES⁺)=557 (M+H+).

Example 2(2-Chloro-4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)boronicacid

Step 1:6-(N-(3-Chloro-4-nitrophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide

A mixture of2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(2.00 g, 4.77 mmol), 2-chloro-4-fluoronitrobenzene (1.68 g, 9.55 mmol),and potassium carbonate (1.98 g, 14.3 mmol) in 4:1 DME/water (20 mL) ina sealed vessel was heated to 100° C. with stirring. After 18 hours themixture was treated with an additional 2.00 g portion of potassiumcarbonate, heated at 100° C. for another 15 hours, and then stirred atRT for 3 days. The mixture was partitioned between EtOAc and water.After separating the phases, the aqueous portion was extracted with twoadditional portions of EtOAc. The combined EtOAc solutions were washedwith water (2×), brine (1×), dried over sodium sulfate and concentratedto dryness at reduced pressure. The crude material was subjected toflash chromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) toafford a tacky, yellow foam. This material was crystallized fromhexane/EtOAc to give the title compound (1.78 g, 65%) as a light yellowsolid. LCMS (m/z, ES⁺)=574 (M+H+).

Step 2:6-(N-(4-Amino-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide

A solution of6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide(0.500 g, 0.870 mmol) in 3:1 MeOH/THF (30 mL) was subjected tohydrogenation at 45 psi in the presence of 5% sulfided platinum oncarbon (50 mg). After 18 hours the reaction vessel was purged withnitrogen, catalyst removed by filtration through celite and the filtrateconcentrated to dryness at reduced pressure. The residue wasrecrystallized from hexane/EtOAc to afford the title compound (0.45 g,95%) as an off-white solid. LCMS (m/z, ES⁺)=544 (M+H+).

Step 3:6-(N-(4-Bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide

A stirred suspension of6-(N-(4-amino-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide(0.421 g, 0.773 mmol) in 25 mL of acetonitrile was treated with 25 mL of48% aqueous HBr and the resulting suspension cooled in an ice waterbath. To the mixture was added a solution of sodium nitrite (0.056 g,0.812 mmol) in 2 mL of water. After stirring at 0° C. for 30 minutes anadditional 14 mg portion of sodium nitrite in 1 mL of water was added.After stirring at 0° C. for another 30 minutes, the mixture was treatedwith CuBr (0.130 g, 0.906 mmol) in four portions over 5 minutes. Themixture was warmed to 60° C. for 30 minutes and then cooled to RT. Themixture was partitioned between EtOAc and 5% aqueous sodium bisulfite.The EtOAc solution was washed with 5% aqueous sodium bisulfite (2×),saturated aqueous sodium bicarbonate (2×), brine (1×), dried over sodiumsulfate and concentrated to dryness at reduced pressure. The crudeproduct was purified by flash chromatography (silica gel, gradient fromhexane to 3:7 hexane/EtOAc) followed by recrystallization fromhexane/EtOAc to give the title compound (0.212 g, 45%) as a white solid.LCMS (m/z, ES⁺)=609 (M+H+).

Step 4:(2-Chloro-4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid

A mixture of6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide(0.205 g, 0.337 mmol), bis(pinacolato)diboron (0.428 g, 1.69 mmol),potassium acetate (0.165 g, 1.69 mmol) and Pd(II)(dppf)Cl₂dichloromethane complex (0.0138 g, 0.017 mmol) in anhydrous 1,4-dioxane(4 mL) in a sealed tube was sparged with nitrogen for 10 minutes. Thevessel was sealed and heated in an 80° C. oil bath with stirring. After4 hours the mixture was cooled to RT and diluted with EtOAc. Theresulting solution was washed with water (2×), saturated brine (1×), anddried over sodium sulfate. While stirring with sodium sulfate, celitewas added to facilitate removal of the insoluble black material thatremained suspended in solution. The mixture was filtered through amedium frit to afford a golden-brown filtrate that was concentrated todryness at reduced pressure. The residue was dissolved in 10 mL of THFand the resulting solution cooled in an ice water bath. The solution wastreated with 1N aqueous HCl (4 mL) followed by sodium periodate (1.08 g,5.05 mmol). The mixture was stirred at 0° C. for 10 minutes and thenallowed to warm to RT. After 18 hours the mixture was partitionedbetween water and EtOAc and the phases separated. The aqueous solutionwas extracted with EtOAc (2×). The combined EtOAc solutions were washedwith 5% aqueous sodium bisulfite (4×), saturated brine (2×), dried oversodium sulfate and concentrated to dryness at reduced pressure. Theresidue was subjected to flash chromatography (silica gel, 2-partgradient: DCM to EtOAc over 15 minutes, then switch solvents to A=9:1DCM/MeOH, B=DCM; gradient from 100% B to 65% A over 4 minutes, then 65%A isocratic for 15 minutes) to give a light tan foam (0.142 g). Thismaterial was dissolved in acetonitrile (3 mL) and the solution stirredwith dropwise addition of 0.25 N aqueous HCl (10 mL) over a 20 minuteperiod. A white suspension was produced which was stirred at RT. After 2hours the solid was collected by filtration in a medium fritted funnel.The filter cake was washed with water (2×), suction air dried for 30minutes, and then dried in vacuo overnight to afford the title compound(0.119 g, 62%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.50(q, 1H) 8.32 (s, 2H) 8.11 (s, 1H) 7.92 (d, 2H) 7.62 (d, 2H) 7.30-7.45(m, 3H) 7.19 (s, 1H) 3.40 (s, 3H) 2.83 (d, 3H) 2.06-2.16 (m, 1H)0.72-1.07 (m, 3H) 0.52 (br s, 1H). LCMS (m/z, ES⁺)=573 (M+H+).

Example 34-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronicacid

Step 1:6-(N-(4-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide(500 mg, 1.244 mmol), 4-bromophenylboronic acid (1.5 g, 7.464 mmol),copper(II) acetate monohydrate (372 mg, 1.866 mmol), triethylamine (252mg, 2.488 mmol), and 4 Å molecular sieves (1 g) in dichloromethane (160mL) was stirred for 2 days. The solution was filtered, concentrated todryness, and purified by column chromatography to afford6-(N-(4-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(180 mg, 0.323 mmol, 26% yield) as a brown solid. LCMS (m/z, ES⁺)=557,559 (M+H+).

Step 2:5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide

A suspension of6-(N-(4-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(150 mg, 0.269 mmol), potassium acetate (80 mg, 0.807 mmol),bis(pinacolato)diboron (205 mg, 0.807 mmol), and Pd(dppf)Cl₂dichloromethane complex (22 mg, 0.027 mmol) in 1,4-dioxane (20 mL) wasmaintained at 95° C. with stirring overnight. The solution was cooled toroom temperature, filtered, concentrated to dryness, and purified bycolumn chromatography to afford5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide(152 mg, 0.251 mmol, 94% yield) as a brown solid. LCMS (m/z, ES⁺)=605(M+H+)

Step 3:4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronicacid

A suspension of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide(152 mg, 0.251 mmol), polymer-supported benzeneboronic acid (480 mg,1.255 mmol), and aqueous 5N HCl (0.35 mL, 1.757 mmol) in tetrahydrofuran(15 mL) was stirred at room temperature for 48 hours. The solution wasfiltered, concentrated to dryness, and purified by reverse phase HPLC toafford4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronicacid (45 mg, 0.086 mmol, 34% yield) as a white solid. ¹H NMR(METHANOL-d₄) δ: 7.98 (d, 1H), 7.96 (d, 1H), 7.87 (S, 1H), 7.66 (d, 2H),7.46 (d, 2H), 7.32-7.26 (m, 3H), 3.33 (s, 3H), 2.99 (s, 3H), 2.22-2.18(m, 1H), 1.10-0.37 (m, 4H). LCMS (m/z, ES⁺)=523 (M+H+)

Example 43-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronicacid

Step 1:6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide(500 mg, 1.24 mmol), 3-bromophenylboronic acid (1.5 g, 7.46 mmol),copper(II) acetate monohydrate (372 mg, 1.87 mmol), triethylamine (252mg, 2.49 mmol), 4 Å molecular sieves (1 g) in dichloromethane (160 mL)was stirred for 2 days. The solid was filtered off, the filtrate wasconcentrated to dryness and purified by column chromatography to afford6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(270 mg, 0.48 mmol, 39% yield) as a brown solid. LCMS (m/z, ES⁺)=557,559 (M+H+).

Step 2:5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide

A suspension of6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(240 mg, 0.43 mmol), potassium acetate (128 mg, 1.29 mmol),bis(pinacolato)diboron (328 mg, 1.29 mmol), and Pd(dppf)Cl₂dichloromethane complex (35 mg, 0.043 mmol) in 1,4-dioxane (20 mL) wasmaintained at 95° C. with stirring overnight. The reaction mixture wascooled to room temperature and the solid was filtered off. The filtratewas concentrated to dryness and purified by column chromatography toafford5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide(269 mg, 0.45 mmol, 92% yield) as a brown solid. LCMS (m/z, ES⁺)=605(M+H+)

Step 3:3-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronicacid

A suspension of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide(269 mg, 0.45 mmol), polymer-supported benzeneboronic acid (770 mg, 2.23mmol), aqueous 5N HCl (0.62 mL, 3.12 mmol) in tetrahydrofuran (15 mL)was stirred at room temperature for 48 hours. The mixture was filtered,the filtrate was concentrated to dryness and purified by reverse phaseHPLC to afford3-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronicacid (41 mg, 0.078 mmol, 17% yield) as a white solid. ¹H NMR(METHANOL-d₄) δ 7.99-7.95 (m, 2H), 7.94 (s, 1H), 7.77-7.38 (m, 4H),7.32-7.25 (m, 3H), 3.32 (s, 3H), 2.98 (s, 3H), 2.29-2.25 (m, 1H),1.10-0.37 (m, 4H). LCMS (m/z, ES⁺)=523 (M+H+).

Example 54-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronicacid

Step 1:5-cyclopropyl-6-(N-(3-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of 2,4-difluoro-1-nitrobenzene (261 mg, 1.64 mmol) and5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide(600 mg, 1.49 mmol) in dimethoxyethane (0.8 mL) and water (0.2 mL) wastreated with potassium carbonate (616.86 mg, 4.47 mmol) and heated to100° C. for 24 hours. The reaction mixture was concentrated and purifiedby column chromatography to afford5-cyclopropyl-6-(N-(3-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(230 mg, 0.43 mmol, 29% yield) as a yellow powder. LCMS (m/z, ES⁺)=542(M+H+)

Step 2:6-(N-(4-amino-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of5-cyclopropyl-6-(N-(3-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(230 mg, 0.43 mmol) and stannous chloride (291 mg, 1.29 mmol) in ethylacetate (5 mL) and ethanol (5 mL) was maintained at reflux for 3 hours.The mixture was cooled to room temperature and partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate,filtered, concentrated to dryness, and purified by column chromatographyto afford6-(N-(4-amino-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(200 mg, 0.39 mmol, 90% yield) as a yellow powder. LCMS (m/z, ES⁺)=512(M+H+)

Step 3:6-(N-(4-bromo-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of6-(N-(4-amino-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(200 mg, 0.39 mmol) in acetonitrile (5 mL) and aqueous hydrogen bromidesolution (5 mL) was treated with an aqueous sodium nitrite (29.6 mg,0.43 mmol) solution at 0° C. with stirring for 0.5 hours. Cuprousbromide (64.3 mg, 0.45 mmol) was then added to the solution in portionsat 0° C., and heated to reflux for 2 hours. The solution was cooled toroom temperature and partitioned between ethyl acetate and water. Theorganic layer was separated, dried over sodium sulfate, filtered,concentrated to dryness, and purified by column chromatography to afford6-(N-(4-bromo-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(140 mg, 0.24 mmol, 61% yield) as a white solid. LCMS (m/z, ES⁺)=575,577 (M+H+)

Step 4:5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of6-(N-(4-bromo-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(140 mg, 0.24 mmol) and bis(pinacolato)diboron (914 mg, 3.60 mmol) inanhydrous dioxane (5 mL) was treated with PdCl₂(dppf) (19.6 mg, 0.024mmol), potassium acetate (47.04 mg, 0.48 mmol) and maintained under N₂with stirring at 90° C. for 4 hours. The suspension was cooled to roomtemperature and partitioned between ethyl acetate and water. The organiclayer was separated, dried over sodium sulfate, filtered, concentratedto dryness, and purified by column chromatography to afford5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(140 mg, 0.22 mmol, 56% yield) as a white solid. LCMS (m/z,ES⁺)=623(M+H+)

Step 5:4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronicacid

A solution of5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(140 mg, 0.22 mmol) and 1N aqueous HCl (2 mL) in anhydrous THF (10 mL)was treated with polymer-supported benzeneboronic acid (5000 mg) andstirred at room temperature for 24 hours. The mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, driedover sodium sulfate, filtered, concentrated to dryness, and purified byreverse phase HPLC to afford4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronicacid (50 mg, 0.092 mmol, 42% yield) as a white solid. ¹H NMR (300 MHz,METHANOL-d4) δ 7.96 (dd, 2H), 7.83 (s, 1H), 7.45-7.15 (m, 6H), 3.43 (s,3H), 2.96 (s, 3H), 2.12 (m, 1H), 1.01-0.52 (m, 4H). LCMS (m/z, ES+)=541(M+H+)

Example 64-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorophenylboronicacid

Step 1:5-cyclopropyl-6-(N-(2-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide(402 mg, 1 mmol), 1,2-difluoro-4-nitrobenzene (318 mg, 2 mmol) andpotassium carbonate (414 mg, 3 mmol) in 1,2-dimethoxyethane (20 mL) andwater (5 mL) was heated at 100° C. for 48 hours. The solution was cooledto room temperature and concentrated, diluted with ethyl acetate (50 mL)and washed with water. The organic layer was dried over sodium sulfate,filtered, concentrated to dryness, and purified by column chromatographyto afford5-cyclopropyl-6-(N-(2-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(420 mg, 0.77 mmol, 77% yield) as a yellow solid. LCMS (m/z, ES⁺)=542(M+H+)

Step 2:6-(N-(4-amino-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of5-cyclopropyl-6-(N-(2-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(420 mg, 0.77 mmol) and tin(II) chloride dihydrate (519 mg, 2.31 mmol)in ethyl acetate (15 mL) and ethanol (15 mL) was heated at 80° C. for 2hours. The solution was cooled to room temperature and concentrated,diluted with ethyl acetate (50 mL) and washed with sodium carbonatesolution. The organic layer was dried over sodium sulfate, filtered,concentrated to dryness, and purified by column chromatography to afford6-(N-(4-amino-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(360 mg, 0.7 mmol, 91% yield) as a yellow solid. LCMS (m/z, ES⁺)=512(M+H+).

Step 3:6-(N-(4-bromo-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of6-(N-(4-amino-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(360 mg, 0.7 mmol) in acetonitrile (20 mL) was added hydrobromic acid (5mL, 40% in water) followed by sodium nitrite (49 mg, 0.77 mmol in 2 mLwater) dropwise at 0° C. After stirring for 10 minutes at 0° C., cuprousbromide (115 mg, 0.8 mmol) was added. The mixture was warmed to 80° C.and stirred for 1 hour. The mixture was cooled to room temperature anddiluted with water (20 mL). The aqueous layer was extracted with ethylacetate (3×20 mL), dried over sodium sulfate, filtered, concentrated todryness, and purified by column chromatography to afford6-(N-(4-bromo-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(240 mg, 0.42 mmol, 60% yield) as an off-white solid. LCMS (m/z,ES⁺)=575, 577 (M+H+).

Step 45-cyclopropyl-6-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of6-(N-(4-bromo-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(240 mg, 0.42 mmol), potassium acetate (123 mg, 1.26 mmol),bis(pinacolato)diboron (533 mg, 2.1 mmol) and PdCl₂(dppf) (68.5 mg,0.084 mmol) in 1,4-dioxane (30 mL) was heated at 100° C. under nitrogenwith stirring for 16 h. The solution was cooled to room temperature,filtered, concentrated, and purified by column chromatography to afford5-cyclopropyl-6-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(200 mg, 0.32 mmol, 76% yield) as a light yellow solid. LCMS (m/z,ES⁺)=623 (M+H+).

Step 5:4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorophenylboronicacid

A suspension of5-cyclopropyl-6-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(200 mg, 0.32 mmol), polymer supported benzeneboronic acid (600 mg, 1.60mmol) and aqueous 5N HCl (0.45 mL, 2.24 mmol) in tetrahydrofuran (20 mL)was stirred at room temperature for 24 h. The solution was filtered,concentrated to dryness, and purified by reverse phase HPLC to afford4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorophenylboronicacid (61 mg, 0.11 mmol, 35% yield) as a white solid. ¹H NMR(METHANOL-d₄) δ 8.03 (s, 1H), 7.97-7.79 (m, 2H), 7.57 (dd, 3H), 7.24(dd, 3H), 3.29 (s, 3H), 2.94 (s, 3H), 2.42 (s, 1H), 1.00 (d, 2H), 0.69(s, 2H). LCMS (m/z, ES⁺)=541 (M+H+).

Example 74-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronicacid

Step 1:6-(N-(4-(benzyloxy)-3-fluorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide

A mixture of2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(2.0 g, 4.77 mmol), (4-(benzyloxy)-3-fluorophenyl)boronic acid (1.762 g,7.16 mmol), Cu(OAc)₂(1.301 g, 7.16 mmol), triethylamine (3.33 mL, 23.87mmol) and powdered 3 Å molecular sieves (2 g) in CH₂Cl₂ (60 mL) wasstirred in a flask open to the air and equipped with a drying tube.After 12 hours the mixture was treated with additional(4-(benzyloxy)-3-fluorophenyl)boronic acid (1.762 g, 7.16 mmol) andCu(OAc)₂(1.301 g, 7.16 mmol) and stirred at room temperature for 4 d.The mixture was diluted with CH₂Cl₂, filtered through Celite and thedark brown filtrate was concentrated to dryness. The crude material waspurified by flash chromatography on silica gel (0-4% EtOAc/CH₂Cl₂) toafford the desired compound which was further purified by flashchromatography on silica gel eluted (0-40% EtOAc/hexane) to give thedesired compound as a light-tan solid (406 mg, 14%). LCMS (m/z, ES⁺)=619(M+H+).

Step 2:2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-hydroxyphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(4-(benzyloxy)-3-fluorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide(350 mg, 0.565 mmol) was dissolved in ethyl acetate (8.0 mL) and ethanol(8.0 mL). 10% of Pd/C (30.1 mg, 0.283 mmol) was added followed by theaddition of H₂ (1 atmosphere, balloon). The mixture was stirred for 2 hat RT and filtrated through Celite. The filtrate was concentrated todryness and rinsed twice with hexane to give the desired product as awhite solid which was used without further purification. LCMS (m/z,ES⁺)=529 (M+H+).

Step 3:4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenyltrifluoromethanesulfonate

Tf₂O (0.157 mL, 0.930 mmol) in CH₂Cl₂ (1 mL) was added dropwise to asuspension of2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-hydroxyphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide(328 mg, 0.620 mmol) and pyridine (0.251 mL, 3.10 mmol) in CH₂Cl₂ (5 mL)under N₂ at room temperature. The mixture was stirred at roomtemperature for 3 h then water was added. The mixture was extracted withCH₂Cl₂ and the combined organic phases were dried over Na₂SO₄, filtered,concentrated at reduced pressure, and purified by flash chromatographyon silica gel eluted (0-40% EtOAc/hexane) to give the desired compoundas a white solid (410 mg, 83% yield). LCMS (m/z, ES⁺)=661 (M+H+).

Step 4:2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

A mixture of4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenyltrifluoromethanesulfonate (170 mg, 0.257 mmol), potassium acetate (76mg, 0.772 mmol), bis(pinacolato)diboron (98 mg, 0.386 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (10.50 mg, 0.013 mmol) in 1,4-dioxane (2.0 ml)was heated at 80° C. in a seal tube under N₂ overnight. The mixture wascooled to room temperature, diluted with EtOAc, and filtered through apad of silica gel and Celite. The filtrate was concentrated to drynessto give the crude product as tan foam which was used without furtherpurification. LCMS (m/z, ES⁺)=639 (M+H+).

Step 5:(4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenyl)boronicacid

Sodium periodate (549 mg, 2.57 mmol) was added to a mixture of2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide(164 mg, 0.257 mmol) in THF (6 mL) and 1N HCl (3.21 mL, 3.21 mmol). Themixture was stirred at room temperature overnight and EtOAc and waterwere added. The aqueous layer was extracted with EtOAc (2×) and thecombined organic phases were washed with 10% aq. Na₂S₂O₃, brine, driedover Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by reverse phase HPLC (MeCN/H₂O with 0.1% TFA) to give thetitle compound as a white solid (80 mg, 56%). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.52 (q, 1H) 8.23 (br. s., 1H) 8.07 (s, 1H) 7.94 (d, 2H) 7.64 (d,2H) 7.55 (t, 1H) 7.22 (s, 1H) 7.11 (s, 1H) 7.07-7.10 (m, 1H) 3.45 (s,4H) 2.85 (d, 3H) 2.04-2.15 (m, 1H) 1.00 (br. s., 1H) 0.82 (d, 2H) 0.54(br. s., 1H). LCMS (m/z, ES⁺)=557 (M+H+).

Example 86-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)pyridin-3-ylboronicacid

Step 1:6-(N-(5-bromopyridin-2-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide(400 mg, 1.00 mmol) in dimethylformamide (5 mL) at 0° C. was addedlithium bis(trimethylsilyl)amide (1.5 mL, 1.50 mmol). After 1 hour5-bromo-2-fluoropyridine (350 mg, 2.00 mmol) was added and stirring wasmaintained at 80° C. for 16 hours. The solution was cooled to roomtemperature, diluted with water, and extracted with ethyl acetate (3×50mL). The combined extracts were washed with brine, dried over sodiumsulfate and concentrated to dryness at reduced pressure. The crudematerial was purified by column chromatography to afford6-(N-(5-bromopyridin-2-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(430 mg, 0.775 mmol, 77.5% yield) as a yellow solid. LCMS (m/z, ES⁺)=559(M+H+).

Step 2:5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylsulfonamido)benzofuran-3-carboxamide

A suspension of6-(N-(5-bromopyridin-2-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(400 mg, 0.72 mmol), potassium acetate (210 mg, 2.14 mmol),bis(pinacolato)diboron (2721 mg, 10.71 mmol), and PdCl₂(dppf) (58 mg,0.071 mmol) in 1,4-dioxane (10 mL) in a thick-walled glass pressurevessel was maintained at 90° C. with stirring for 16 hours. The solutionwas cooled to room temperature and filtered. The filtrates wereconcentrated and purified by column chromatography to afford5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylsulfonamido)benzofuran-3-carboxamide(320 mg, 0.53 mmol, 74% yield) as a white solid. LCMS (m/z, ES⁺)=606(M+H+).

Step 3:6-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)pyridin-3-yl)boronicacid

A suspension of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylsulfonamido)benzofuran-3-carboxamide(320 mg, 0.53 mmol), polymer-supported benzeneboronic acid (862 mg, 2.65mmol) and 5N aqueous HCl (0.74 mL, 3.78 mmol) in tetrahydrofuran (10 mL)was stirred at room temperature for 48 h. The solution was filtered,concentrated to dryness, and purified by reverse phase HPLC to afford6-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)pyridin-3-yl)boronicacid (80 mg, 0.153 mmol, 29% yield) as a white solid. ¹H NMR (300 MHz,METHANOL-d₄) δ 8.36 (s, 1H), 7.72 (m, 3H), 7.57 (s, 1H), 7.25-7.1 (m,3H), 6.90-6.87 (m, 1H), 3.59 (s, 3H), 3.03 (s, 3H), 2.13-2.09 (m, 1H),1.07-1.03 (m, 2H), 0.70 (m, 2H). LCMS (m/z, ES+)=524 (M+H+).

Example 9(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronicacid

Step 1: 2-(difluoromethyl)-4-fluoro-1-nitrobenzene

Diethylaminosulfur trifluoride (0.78 mL, 5.91 mmol) was added slowly toa 0° C. solution of 5-fluoro-2-nitrobenzaldehyde (1 g, 5.91 mmol) indichloromethane (30 mL). The reaction mixture was stirred for 10 min at0° C., 2.5 h at room temperature, cooled to 0° C. and quenched by theslow addition of saturated aqueous NaHCO₃. The aqueous layer wasextracted with dichloromethane. The combined organic layers were dried(Na₂SO₄), filtered and evaporated to afford2-(difluoromethyl)-4-fluoro-1-nitrobenzene (1.13 g, quant.) as a brownliquid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.26 (dd, 1H), 7.60 (dd,1H), 7.28-7.56 (m, 2H).

Step 2:5-cyclopropyl-6-(N-(3-(difluoromethyl)-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(1.00 g, 2.49 mmol), 2-(difluoromethyl)-4-fluoro-1-nitrobenzene (1.13 g,5.91 mmol) and K₂CO₃ (0.85 g, 6.15 mmol) in HMPA (6.2 mL) was stirred at60° C. for 15 h. The reaction mixture was diluted with EtOAc and water.The organic layer was washed with brine, dried (Na₂SO₄), filtered,evaporated and purified by silica gel chromatography (0-80%EtOAc/hexanes) to afford the title compound (1.45 g, 97%) as a yellowsolid. LCMS (m/z, ES⁺)=574.3 (M+H+).

Step 3:6-(N-(4-amino-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of5-cyclopropyl-6-(N-(3-(difluoromethyl)-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(1.45 g, 2.53 mmol) and 10% Pd/C (catalytic) in MeOH (15 mL) was stirredunder a hydrogen atmosphere (20 psi) for 3 h. The reaction mixture wasfiltered through celite, evaporated, and purified by silica gelchromatography (0-50% EtOAc/hexanes) to afford the title compound (0.87g, 63%) as a white solid. LCMS (m/z, ES⁺)=544.3 (M+H+).

Step 4:6-(N-(4-bromo-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Sodium nitrite (0.12 g, 1.75 mmol) was added to a 0° C. solution of6-(N-(4-amino-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.87 g, 1.59 mmol) in acetonitrile (10 ml) and aq HBr (48%) (10 mL).The reaction mixture was stirred for 30 min at 0° C. and copper (I)bromide (0.27 g, 1.91 mmol) was added. The reaction mixture was stirredat 75° C. for 2 h and diluted with EtOAc and water. The organic layerwas washed with brine, dried (Na₂SO₄), filtered, evaporated and purifiedby silica gel chromatography (0-50% EtOAc/hexanes) to afford the titlecompound (0.38 g, 39%) as a white foam. LCMS (m/z, ES⁺)=607, 609 (M+H+).

Step 5:(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronicacid

A solution of6-(N-(4-bromo-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.20 g, 0.33 mmol), potassium acetate (0.13 g, 1.32 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (0.027 g, 0.033 mmol), andbis(pinacolato)diboron (0.25 g, 0.99 mmol) in 1,4-dioxane (4.12 ml) wasdegassed, purged with nitrogen and heated at 80° C. for 3 h 45 mins. Thereaction mixture was diluted with EtOAc and water, filtered throughcelite, and evaporated. The brown residue was dissolved in 10 mL THF,and 5 mL 1M HCl. NaIO₄ (0.56 g, 2.63 mmol) was added and the suspensionwas stirred for 1 h and diluted with EtOAc and water. The organic layerwas washed with water, brine, dried (Na₂SO₄), filtered, evaporated andpurified by reverse phase chromatography (5-100% CH₃CN/H₂O (0.1% formicacid)) to afford the title compound (0.085 g, 45%) as a white solid. ¹HNMR (400 MHz, METHANOL-d4) δ ppm 7.90-7.97 (m, 2H), 7.87 (s, 1H),7.43-7.61 (m, 3H), 7.30 (s, 1H), 7.21-7.29 (m, 2H), 6.65-7.01 (m, 1H),3.33 (s, 3H), 2.94 (s, 3H), 2.08-2.21 (m, 1H), 0.35-1.10 (m, 4H). LCMS(m/z, ES⁺)=573.3 (M+H+).

Example 10(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(trifluoromethyl)phenyl)boronicacid

Step 1:5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-nitro-3-(trifluoromethyl)phenyl)methylsulfonamido)benzofuran-3-carboxamide

A solution of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(1.00 g, 2.49 mmol), 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (1.04g, 4.97 mmol), K₂CO₃ (1.03 g, 7.45 mmol) in HMPA (6.2 mL) was stirred at60° C. for 15 h. The reaction mixture was diluted with EtOAc and water.The organic layer was washed with brine, dried (Na₂SO₄), filtered,evaporated and purified by silica gel chromatography (0-50%EtOAc/hexanes) to afford the title compound (1.37 g, 93%) as an orangesolid. LCMS (m/z, ES⁺)=592.2 (M+H+).

Step 2:6-(N-(4-amino-3-(trifluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-nitro-3-(trifluoromethyl)phenyl)methylsulfonamido)benzofuran-3-carboxamide(1.37 g, 2.31 mmol) and 10% Pd/C (catalytic) in MeOH (23 mL) was stirredunder a hydrogen atmosphere (10 psi) for 1 h. The reaction mixture wasfiltered through celite, evaporated, and purified by silica gelchromatography (0-50% EtOAc/hexanes) to afford the title compound (1.3g, quant.) as a white solid. LCMS (m/z, ES⁺)=562.3 (M+H+).

Step 3:6-(N-(4-bromo-3-(trifluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Sodium nitrite (0.18 g, 2.55 mmol) was added to a 0° C. solution of6-(N-(4-amino-3-(trifluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(1.3 g, 2.32 mmol) in acetonitrile (14 ml) and aq HBr (48%) (14 mL). Thereaction mixture was stirred for 30 min at 0° C. and copper (I) bromide(0.40 g, 2.78 mmol) was added. The reaction mixture was stirred at 60°C. for 1 h and diluted with EtOAc and water. The organic layer waswashed with brine, dried (Na₂SO₄), filtered, evaporated and purified bysilica gel chromatography (0-50% EtOAc/hexanes) to afford the titlecompound (1.06 g, 73%) as a white foam. LCMS (m/z, ES⁺)=625.2, 627.2(M+H+).

Step 4:(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(trifluoromethyl)phenyl)boronicacid

A solution of6-(N-(4-bromo-3-(trifluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.20 g, 0.32 mmol), potassium acetate (0.13 g, 1.28 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (0.026 g, 0.032 mmol), bis(pinacolato)diboron(0.24 g, 0.96 mmol) in 1,4-dioxane (4 ml) was degassed, purged withnitrogen and heated at 80° C. for 4 h. The reaction mixture was dilutedwith EtOAc and water, filtered through celite, and evaporated. The brownresidue was dissolved in 10 mL THF, and 5 mL 1M HCl. NaIO₄ (0.64 g, 3.20mmol) was added and the suspension was stirred for 3 h and diluted withEtOAc and water. The organic layer was washed with water, brine, dried(Na₂SO₄), filtered, evaporated and purified by reverse phasechromatography (5-100% CH₃CN/H₂O (0.1% formic acid)) to afford the titlecompound (0.092 g, 49%) as a white solid. ¹H NMR (400 MHz, METHANOL-d4)δ ppm 7.85-8.00 (m, 3H), 7.59-7.72 (m, 2H), 7.47 (d, 1H), 7.29-7.34 (m,1H), 7.20-7.29 (m, 2H), 3.35 (s, 3H), 2.94 (s, 3H), 2.12 (tt, 1H),0.28-1.10 (m, 4H). LCMS (m/z, ES⁺)=591.3 (M+H+).

Example 11(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2,6-difluorophenyl)boronicacid

Step 1:5-cyclopropyl-6-(N-(3,5-difluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(1.00 g, 2.49 mmol), 1,3,5-trifluoro-2-nitrobenzene (0.91 g, 5.11 mmol),K₂CO₃ (1.06 g, 7.67 mmol) in HMPA (7 mL) was stirred at 50° C. for 8 h.An additional portion of 1,3,5-trifluoro-2-nitrobenzene (0.91 g, 5.11mmol) was added and the reaction mixture was stirred at 50° C. foranother 15 h. The reaction mixture was diluted with EtOAc and water. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered, andevaporated. The residue was taken up in 1:1 CH2Cl2:acetone. The desiredisomer precipitated out and was collected by vacuum filtration and driedto afford the title compound (0.92 g, 65%) as a white solid. LCMS (m/z,ES⁺)=560.2 (M+H).

Step 2:6-(N-(4-amino-3,5-difluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of5-cyclopropyl-6-(N-(3,5-difluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.65 g, 1.16 mmol) and tin (II) chloride (0.66 g, 3.49 mmol) in EtOAc(10 mL) and ethanol (10 mL) was heated under reflux for 2 h. Thereaction mixture was diluted with EtOAc and water and the suspension wasfiltered through celite. The organic layer was dried (Na₂SO₄), filtered,evaporated and purified by silica gel chromatography (0-50%EtOAc/hexanes) to afford the title compound (0.34 g, 55%) as a whitesolid. LCMS (m/z, ES⁺)=530.2 (M+H+).

Step 3:6-(N-(4-bromo-3,5-difluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Sodium nitrite (0.034 g, 0.49 mmol) was added to a 0° C. solution of6-(N-(4-amino-3,5-difluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.235 g, 0.444 mmol) in Acetonitrile (3 ml) and aq HBr (48%) (3 mL).The reaction mixture was stirred for 30 min at 0° C. and copper (I)bromide (0.076 g, 0.53 mmol) was added. The reaction mixture was stirredat 90° C. for 2 h and diluted with EtOAc and water. The organic layerwas washed with brine, dried (Na₂SO₄), filtered, evaporated and purifiedby silica gel chromatography (0-50% EtOAc/hexanes) to afford the titlecompound (0.094 g, 36%) as a white foam. LCMS (m/z, ES⁺)=593.2, 595.2(M+H+).

Step 4:(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2,6-difluorophenyl)boronicacid

A solution of6-(N-(4-bromo-3,5-difluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.093 g, 0.157 mmol), potassium acetate (0.062 g, 0.627 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (0.013 g, 0.016 mmol), bis(pinacolato)diboron(0.080 g, 0.31 mmol) in 1,4-Dioxane (1.6 ml) was degassed, purged withnitrogen and heated at 90° C. for 4 h. The reaction mixture was dilutedwith EtOAc and water, filtered through celite, and evaporated. The brownresidue was dissolved in 5 mL THF, and 2.5 mL 1M HCl. NaIO₄ (0.27 g,1.25 mmol) was added and the suspension was stirred for 2.5 h anddiluted with EtOAc and water. The organic layer was washed with water,brine, dried (Na₂SO₄), filtered, evaporated and purified by reversephase chromatography (5-100% CH₃CN/H₂O (0.1% formic acid)) to afford thetitle compound (0.017 g, 19%) as a white solid. ¹H NMR (400 MHz,METHANOL-d4) δ ppm 7.91-7.98 (m, 2H), 7.79 (s, 1H), 7.34 (s, 1H),7.20-7.29 (m, 2H), 6.82-6.92 (m, 2H), 3.38 (s, 3H), 2.95 (s, 3H),2.01-2.11 (m, 1H), 0.70-1.07 (m, 3H), 0.54 (br. s., 1H). LCMS (m/z,ES⁺)=559.3 (M+H+).

Example 12(2-cyano-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid

Step 1:6-(N-(3-cyano-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of 5-fluoro-2-nitrobenzonitrile (1.280 mL, 11.18 mmol),5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(3.0 g, 7.45 mmol) and K₂CO₃ (3.09 g, 22.36 mmol) in 1,2-dimethoxyethane(30 mL) and water (7.5 mL) in a seal tube was heated to 80° C.overnight. It was cooled down to room temperature, diluted with EtOAc,filtered and the off-white solid was washed with water and then dried invacuo to give crude desired product as a yellow solid (80% purity, 3.9g, 76%). LCMS (m/z, ES⁺)=549 (M+H+)

Step 2:6-(N-(4-amino-3-cyanophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of Na₂S₂O₄ (7.24 g, 41.6 mmol) in water (70 mL) was addeddropwise to a solution of6-(N-(3-cyano-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(3.8 g, 6.93 mmol) in THF at room temperature under N₂. The mixture wasstirred overnight. H₂O was added to the mixture and then extracted withEtOAc. The combined extracts were washed with brine, dried over Na₂SO₄.After concentration, the crude residue was purified by chromatography onsilica gel eluted with 0-20% EtOAC in DCM to give the desired product asa white solid (2.67 g, 74.3%). LCMS (m/z, ES⁺)=519 (M+H+)

Step 3:6-(N-(4-bromo-3-cyanophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

tBuNO₂ (0.859 ml, 7.23 mmol) was added dropwise to a solution of CuBr₂(1.292 g, 5.79 mmol) in acetonitrile (10 mL). The mixture was heated to50° C. for 10 min and then a suspension of6-(N-(4-amino-3-cyanophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(1.5 g, 2.89 mmol) in acetonitrile (40 mL) was added portions to abovesolution. It was stirred for 30 min at 50° C. and then cooled to roomtemperature. The reaction was quenched with ice-cooled 1N HCl and thenextracted with EtOAc. The combined extracts were washed with 10% Na₂S₂O₃and brine, and then dried over Na₂SO₄. After concentration, the cruderesidue was purified by chromatography on silica gel eluted with 0-5%EtOAC in DCM to give the desired product as a white foam (1.18 g, 70%).LCMS (m/z, ES⁺)=583 (M+H+)

Step 4:6-(N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of6-(N-(4-bromo-3-cyanophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(100 mg, 0.172 mmol), potassium acetate (67.4 mg, 0.687 mmol),bis(pinacolato)diboron (87 mg, 0.343 mmol) andbis(tricyclohexylphosphine)palladium(II) dichloride (12.67 mg, 0.017mmol) in 1,4-dioxane (2.0 ml) was maintained at 90° C. in a sealed tubeunder N₂ overnight. The mixture was allowed to cool to room temperature,diluted with EtOAc, filtered through a pad of silic gel and celite andthen concentrated to dryness to give the crude product as tan foam whichwas used for the next step without further purification. LCMS (m/z,ES⁺)=630 (M+H+).

Step 5:(2-cyano-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid

The crude6-(N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(108 mg, 0.172 mmol) was dissolved in tetrahydrofuran (4.0 mL). 1M HCl(2.059 mL, 1.029 mmol) was added followed by sodium periodate (294 mg,1.373 mmol). The mixture was stirred at room temperature overnight. Thereaction was partitioned between EtOAc and water. The aqueous layer wasextracted with EtOAc (2×). The organic phase was washed with 10% aq.Na₂S₂O₃, brine, and dried over Na₂SO₄. After concentration, the cruderesidue was purified by reverse phase HPLC (10-100% MeCN/H₂O with 0.1%TFA) to give the title compound as a white solid (58 mg, 62%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.60 (br. s., 1H) 8.48 (q, 1H) 8.12 (s, 1H)7.94-8.02 (m, 2H) 7.73-7.80 (m, 2H) 7.58-7.65 (m, 1H) 7.41 (t, 2H) 7.21(s, 1H) 3.46 (s, 3H) 2.84 (d, 3H) 2.03-2.14 (m, 1H) 0.99 (br. s., 1H)0.85 (br. s., 2H) 0.45 (br. s., 1H). LCMS (m/z, ES⁺)=548 (M+H+).

Example 136-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid

Step 1: ethyl6-((4-bromo-3-chlorophenyl)amino)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate

NEt₃ (0.490 mL, 3.51 mmol) was added to a suspension of(4-bromo-3-chlorophenyl)boronic acid (364 mg, 1.546 mmol) in DCM (7 mL)and the resulting solution was added dropwise to mixture of ethyl6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (500mg, 1.405 mmol), copper(II) acetate (281 mg, 1.546 mmol), 3A molecularsieves (1 g) and NEt₃ (0.490 mL, 3.51 mmol) in DCM (7 mL) stirringvigorously at RT open to the air in a flask equipped with a drying tube.After stirring for 4 h at RT, another solution of NEt₃ (0.490 mL, 3.51mmol) and (4-bromo-3-chlorophenyl)boronic acid (364 mg, 1.546 mmol) inDCM (7 mL) was added dropwise to the reaction mixture, followed by morecopper(II) acetate (281 mg, 1.546 mmol). The reaction mixture wasstirred for 3 d and more solution of NEt₃ (0.490 mL, 3.51 mmol) and(4-bromo-3-chlorophenyl)boronic acid (364 mg, 1.546 mmol) in DCM (7 mL)was added dropwise with further addition of copper(II) acetate (281 mg,1.546 mmol). After 2 h, EtOAc was added followed by Celite. The mixturewas stirred for 30 min then filtered through a pad of Celite and thebrown solution was concentrated to dryness. EtOAc was added followed bywater. The organic layer was separated, washed with water, brine, driedover MgSO₄, filtered and concentrated. The crude product was purified onsilica gel (hex/EtOAc) to give ethyl6-((4-bromo-3-chlorophenyl)amino)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate(685 mg, 1.231 mmol, 88% yield) as an orange foam. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.17 (s, 1H), 7.98-8.07 (m, 2H), 7.58-7.65 (m, 3H),7.49-7.56 (m, 2H), 7.11 (d, 1H), 6.87 (dd, 1H), 4.36 (q, 2H), 1.95-2.12(m, 1H), 1.36 (t, 3H), 0.93-1.05 (m, 2H), 0.57-0.71 (m, 2H).

Step 2: ethyl6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate

A 1M solution of LiHMDS in THF (1.049 mL, 1.049 mmol) was added dropwiseto a solution of ethyl6-((4-bromo-3-chlorophenyl)amino)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate(440 mg, 0.807 mmol) in THF (15 mL) at −78° C. After stirring for 45min, the red solution was added dropwise via cannula to a solution ofMsCl (0.252 mL, 3.23 mmol) in THF (1 mL) at −78° C. Upon completeaddition the yellow solution was allowed to warm to RT and stirredovernight. Water (150 mL) and EtOAc (150 mL) were added. The organiclayer was separated and washed with water, brine, dried over MgSO₄,filtered and concentrated. The crude product was purified on silica gel(hex/EtOAc) to give ethyl6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate(259 mg, 0.395 mmol, 49% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.22(s, 1H), 8.05 (d, 2H), 7.78 (d, 1H), 7.64-7.71 (m, 3H), 7.62 (s, 1H),7.31 (dd, 1H), 4.35 (q, 2H), 3.46 (s, 3H), 2.10-2.22 (m, 1H), 1.34 (t,3H), 0.69-1.13 (m, 3H), 0.42 (br. s., 1H).

Step 3:6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid

A 1M solution of NaOH (1.877 mL, 1.877 mmol) was added to a solution ofethyl6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate(234 mg, 0.375 mmol) in THF (2 mL) and MeOH (1 mL) at RT. After 1 h awhite precipitate formed but starting material is still evident by LCMS.THF (3 mL) and a 4N solution of NaOH (1 mL) were added and the mixturewas heated to 60° C. for 4 h. EtOAc was added and the aqueous layer wasmade acidic with the addition of 1N HCl. The organic layer wasseparated, washed with water, brine, dried over Na₂SO₄, filtered andconcentrated to give6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid (220 mg, 0.351 mmol, 94% yield) as a white solid. LCMS (m/z,ES⁺)=594.0 (M−H).

Step 4:6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid

A flask containing6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid (100 mg, 0.168 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (85 mg,0.336 mmol), potassium acetate (65.9 mg, 0.672 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (13.72 mg, 0.017 mmol) was evacuated andpurged with nitrogen (2×) then 1,4-Dioxane (4 mL) was added and themixture was heated to 90° C. under nitrogen for 16 h. The reaction wascooled to RT, diluted with EtOAc, filtered through Celite and water wasadded. The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated to dryness. The crude product was used as is in next step.

Step 5:6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid

A solution of6-(N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid (110 mg, 0.171 mmol) and sodium periodate (183 mg, 0.856 mmol) inTHF (14 mL) and aqueous 1N HCl (7 mL) was stirred at RT for 4 h thenwater and EtOAc were added. The organic layer was separated, washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by Reverse Phase HPLC (water/ACN+0.1% formic acid) to give6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid (24 mg, 0.041 mmol, 24% yield) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 13.31 (br. s., 1H), 8.33 (s, 2H), 8.16 (s, 1H), 8.03 (d,2H), 7.52-7.70 (m, 3H), 7.37-7.48 (m, 2H), 7.34 (dd, 1H), 3.40 (s, 3H),2.09-2.22 (m, 1H), 0.64-1.11 (m, 3H), 0.47 (br. s., 1H). LCMS (m/z,ES⁺)=558.1 (M−H).

Example 14(4-(N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-6-yl)methylsulfonamido)-2-chlorophenyl)boronicacid

HATU (27.1 mg, 0.071 mmol) was added to a solution of6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid (20 mg, 0.036 mmol) and Hunig's base (0.031 mL, 0.179 mmol) in DMF(3 mL). After stirring for 1 h at RT, a 2M solution of ammonia in MeOH(0.357 mL, 0.714 mmol) was added and the solution was stirred for 16 h.Water and EtOAc were added. The organic layer was separated, washed withwater, brine, dried over Na2SO4, filtered and concentrated. The crudeproduct was purified by Reverse Phase HPLC (water/MeCN+0.1% formic acid)to give(4-(N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-6-yl)methylsulfonamido)-2-chlorophenyl)boronicacid (9 mg, 0.015 mmol, 43% yield) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.33 (s, 2H), 8.12 (s, 1H), 8.05 (s, 1H), 7.94-8.01 (m,2H), 7.80 (s, 1H), 7.59-7.68 (m, 2H), 7.41-7.46 (m, 1H), 7.39 (d, 1H),7.30-7.37 (m, 1H), 7.23 (s, 1H), 3.41 (s, 3H), 2.05-2.21 (m, 1H), 1.02(br. s., 1H), 0.83 (br. s., 2H), 0.53 (br. s., 1H). LCMS (m/z,ES+)=559.2 (M+H+).

Example 156-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate

A solution of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(1.0 g, 2.49 mmol), methyl 5-fluoro-2-nitrobenzoate (0.99 g, 4.97 mmol),and potassium carbonate (1.03 g, 7.45 mmol) in HMPA (6.2 mL) was stirredat 60° C. for 3 days. The solution was diluted with EtOAc and water andthe organic layer was washed with brine, dried (Na₂SO₄), filtered,evaporated and purified by silica gel chromatography (0-80%EtOAc/hexanes) to afford the title compound (1.33 g, 92%) as a yellowsolid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (d, J=9.09 Hz, 1H),7.85-7.92 (m, 2H), 7.56 (s, 1H), 7.53 (s, 1H), 7.50 (dd, J=9.09, 2.64Hz, 1H), 7.43 (d, J=2.64 Hz, 1H), 7.19-7.26 (m, 2H), 5.80 (d, J=4.59 Hz,1H), 3.90 (s, 3H), 3.34 (s, 3H), 3.02 (d, J=4.98 Hz, 3H), 1.91 (tt,J=8.37, 5.31 Hz, 1H), 1.01 (br. s., 1H), 0.89 (br. s., 1H), 0.73-0.85(m, 1H), 0.58 (br. s., 1H).

Step 2: methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

A solution of methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate(1.33 g, 2.29 mmol) and 10% Pd/C (cat.) in MeOH (20 mL) was stirredunder a hydrogen atmosphere (15 psi) for 1.5 h. The solution wasfiltered through celite and evaporated to afford the title compound(1.26 g, quant.) as a light yellow solid that was used without furtherpurification.

Step 3: methyl2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

A solution of methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate(1.60 g, 2.91 mmol) and NCS (0.39 g, 2.91 mmol) in 80 mL CH₃CN wasstirred at 40° C. for 30 mins. Additional NCS (0.39 g, 2.91 mmol) wasadded, the reaction mixture was heated at 40° C. for another 30 mins,evaporated onto silica gel, and purified by silica gel chromatography(0-70% EtOAc/hexanes) to afford the title compound (1.29 g, 76%) as alight pink solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=2.54Hz, 1H), 7.85-7.92 (m, 2H), 7.71 (s, 1H), 7.65 (d, J=2.63 Hz, 1H), 7.43(s, 1H), 7.15-7.22 (m, 2H), 6.36 (br. s., 2H), 5.85 (d, J=4.78 Hz, 1H),3.87 (s, 3H), 3.19 (s, 3H), 2.98 (d, J=4.88 Hz, 3H), 2.15-2.30 (m, 1H),0.31-1.11 (m, 4H).

Step 4: methyl2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

Sodium nitrite (0.17 g, 2.42 mmol) was added to a 0° C. solution ofmethyl2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate(1.29 g, 2.20 mmol) in acetonitrile (7.3 ml) and 48% aqueous HBr (7.3ml) at 0° C. and the reaction mixture was stirred at 0° C. for 30 mins,Copper(I) bromide (0.38 g, 2.64 mmol) was added and the solution washeated at 50° C. for 30 mins. The reaction mixture was cooled to RT,diluted with EtOAc and water. The organic layer was washed with brine,dried (Na₂SO₄), filtered, evaporated and purified by silica gelchromatography (0-50% EtOAc/hexanes) to afford the title compound (1.24g, 86%) as a white foam. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86-7.93(m, 2H), 7.50-7.63 (m, 4H), 7.17-7.25 (m, 2H), 5.79 (br. s., 1H), 3.92(s, 3H), 3.28 (s, 3H), 3.01 (d, J=4.88 Hz, 3H), 1.94-2.04 (m, 1H),0.76-1.09 (m, 3H), 0.55 (br. s., 1H).

Step 5:6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LiBH₄ (2.85 ml, 5.71 mmol) solution (2M in THF) was added dropwise to a0° C. solution of methyl2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate(1.24 g, 1.90 mmol) in Tetrahydrofuran (THF) (13.5 ml) and Methanol (1.3ml). The reaction mixture was stirred at 0° C. for 1 h and quenched with1M NaOH. The reaction mixture was diluted with EtOAc and water. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andevaporated. The crude alcohol was taken up in THF (14 mL). DIEA (1.0 ml,5.71 mmol) and MOM-Cl (0.36 ml, 4.76 mmol) were added and the reactionmixture was stirred at 50° C. overnight. Sat′d NaHCO₃ was added and themixture was extracted with EtOAc. The organic layer was washed withbrine, dried (Na₂SO₄), filtered, evaporated and purified by silica gelchromatography (0-50% EtOAc/hexanes) to obtain the title compound (1.08g, 85%) as a white foam. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86-7.93(m, 2H), 7.61 (s, 1H), 7.50 (d, 1H), 7.49 (s, 1H), 7.42 (d, J=2.83 Hz,1H), 7.18-7.25 (m, 2H), 5.80 (br. s., 1H), 4.73 (s, 2H), 4.62 (s, 2H),3.38 (s, 3H), 3.27 (s, 3H), 3.01 (d, J=4.98 Hz, 3H), 2.05-2.14 (m, 1H),0.75-1.11 (m, 3H), 0.58 (br. s., 1H).

Step 6:6-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.25 g, 0.38 mmol), potassium acetate (0.15 g, 1.50 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (0.031 g, 0.038 mmol), bis(pinacolato)diboron(0.29 g, 1.13 mmol) in 1,4-Dioxane (3.75 ml) was degassed, purged withnitrogen and heated at 90° C. for 15 h. The reaction mixture was dilutedwith EtOAc and water, filtered through celite, and evaporated. The brownresidue was dissolved in THF (5 mL), and 1M HCl (5 mL) and the solutionwas heated at 70° C. for 4 h. MeOH (2 mL) was added and the solution washeated at 70° C. for another 15 h and diluted with EtOAc and water. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered,evaporated and purified by silica gel chromatography (100% EtOAc to 10%MeOH/CH₂Cl₂) to obtain the title compound as a clear oil. MeOH was addedand the precipitate was collected by vacuum filtration, washed with MeOHand dried to afford the title compound (0.0831 g, 39%) as a light tansolid. The filtrate was purified by reverse phase chromatography (5-100%CH₃CN/H₂O (0.1% formic acid)) to afford an additional batch of the titlecompound (0.0146 g, 7%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δppm 9.17 (s, 1H), 8.50 (d, J=4.68 Hz, 1H), 8.09 (s, 1H), 7.94-8.02 (m,2H), 7.37-7.46 (m, 3H), 7.28 (d, J=1.56 Hz, 1H), 7.22 (s, 1H), 4.96 (s,2H), 3.47 (s, 3H), 2.84 (d, J=4.59 Hz, 3H), 2.02-2.14 (m, 1H), 0.98 (br.s., 1H), 0.82 (br. s., 2H), 0.49 (br. s., 1H). LCMS (m/z, ES⁺)=569.2(M+H+).

Example 16(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(methylsulfonyl)phenyl)boronicacid

Step 1:5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(methylthio)-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamide

A mixture of6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(2 g, 3.58 mmol), and sodium thiomethoxide (0.685 g, 9.78 mmol) wasdissolved in 20 mL of 1:1 CH₃CN/Isopropanol and was stirred at roomtemperature for 3 h. Solvent was evaporated and water (60 mL) was added.The yellowish solid formed was filtered, washed with water to providelight yellowish solid which was used in the next step. (1.6 g, 86%) LCMS(m/z, ES⁺)=570 (M+H+).

Step 2:5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(methylsulfonyl)-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamide

To5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(methylthio)-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamide(1 g, 1.756 mmol) in acetic acid (5 mL) was carefully added H₂O₂ (1.630mL, 15.96 mmol). The reaction mixture was stirred at 90° C. for 5 h. Theresulting yellow suspension was concentrated and cooled in an ice bathand sat NaHCO₃ was added. The resulting yellow solid was filtered,washed 3 times (3×15 mL) with water and dried. This material was used inthe next step. (0.8 g, 83%). LCMS (m/z, ES⁺)=602 (M+H+).

Step 3:6-(N-(4-amino-3-(methylsulfonyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(methylsulfonyl)-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamide(0.7 g, 1.164 mmol) in 1:1 EtOH/Ethyl acetate (10 mL) was added tin(II)chloride (1.324 g, 6.98 mmol). The reaction was heated at 70° C. for 3h. Solvent was evaporated and the reaction was partitioned between EtOAcand water. The resulting semi viscous mass was filtered (6 h) and thesolid obtained (0.5 g, 75%) was progressed as is to the next step. LCMS(m/z, ES⁺)=572 (M+H+).

Step 4:6-(N-(4-bromo-3-(methylsulfonyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of6-(N-(4-amino-3-(methylsulfonyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.4 g, 0.700 mmol) in acetonitrile (3 mL) was added 8M HBr (0.437 mL,3.50 mmol). The resulting solution was cooled in an ice water bath for15 minutes and the mixture was treated with a solution of sodium nitrite(0.072 g, 1.050 mmol) in water (2 mL) over 5 min. The resulting yellowsuspension was stirred in an ice bath for 1.5 hours and then treatedwith copper(I) bromide (0.201 g, 1.399 mmol) in small portions over 5minutes. This dark brown solution that was warmed to 60° C. and stirringcontinued for additional 2 h. The mixture was cooled to RT and pouredinto a mixture of 5% aqueous sodium bisulfite (6 mL) and EtOAc (80 mL).The phases were separated and the aqueous solution extracted with twoadditional 15 mL portions of EtOAc. The combined EtOAc solutions werewashed with 5% aqueous sodium bisulfite, saturated aqueous sodiumbicarbonate, saturated brine, dried over sodium sulfate and concentratedto dryness at reduced pressure to give a yellow foam.

This material was subjected to flash chromatography (silica gel,gradient from 9:1 hexane/EtOAc to EtOAc) to afford the title compound(0.3 g, 68%). LCMS (m/z, ES⁺)=635,637 (M+H+).

Step 5:(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(methylsulfonyl)phenyl)boronicacid

To a solution of6-(N-(4-bromo-3-(methylsulfonyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(200 mg, 0.315 mmol) in 1,4-Dioxane (2 mL) wad added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (400 mg,1.574 mmol), potassium acetate (154 mg, 1.574 mmol) and Pd(II)(dppf)Cl₂DCM complex (12.85 mg, 0.016 mmol). The mixture was stirred undernitrogen at 80° C. After 4 hours the mixture was cooled to RT anddiluted with EtOAc (10 mL). The resulting solution was washed withwater, saturated brine, and dried over sodium sulfate. After evaporationof the solvent, the crude residue was dissolved in 10 mL of THF and theresulting solution cooled in an ice water bath. The solution was treatedwith 1N aqueous HCl (1.574 mL, 1.574 mmol) followed by sodium periodate(135 mg, 0.629 mmol). The mixture was stirred at 0° C. for 20 minutesand then allowed to warm to RT. After 18 hours, the mixture waspartitioned between water and EtOAc and the phases separated. Theaqueous solution was extracted with EtOAc. The combined EtOAc solutionswere washed with 5% aqueous sodium bisulfite, saturated brine, driedover sodium sulfate and concentrated to dryness at reduced pressure. Theresidue was subjected to HPLC purification (ACN: Water—0.1% Formic acid)to provide the pure product (12 mg, 6.4%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.97 (br. s., 2H), 7.87 (d, J=5.37 Hz, 2H),7.56-7.64 (m, 2H), 7.49 (s, 1H), 7.15-7.24 (m, 2H), 6.15-6.37 (m, 1H),5.77-5.92 (m, 1H), 3.30 (s, 3H), 3.13 (br. s., 3H), 3.00 (d, J=2.34 Hz,3H), 1.91-2.10 (m, 1H), 1.18-1.34 (m, 1H), 0.95-1.10 (m, 1H), 0.83-0.93(m, 1H), 0.69-0.83 (m, 1H), 0.44-0.61 (m, 1H). LCMS (m/z, ES⁺)=601(M+H+).

Example 171-(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)-4-methyl-2,6,7-trioxa-1-borabicyclo[12.2.2]octan-1-uidepotassium salt

To a stirred solution of(2-chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid (0.0750 g, 0.135 mmol) and 1,1,1-tris(hydroxymethyl)ethane (0.0180g, 0.148 mmol) in anhydrous THF (6 mL) was added activated 3 angstrommolecular sieves (0.400 g). The resulting mixture was heated to refluxfor 4 hours and cooled to RT. The mixture was filtered to remove solidsand the filtrate concentrated to dryness at reduced pressure. Theresidue was dissolved in 5 mL of anhydrous THF and the solution cooledto 0° C. The solution was treated with 1M potassium t-butoxide/THF (135μL, 0.135 mmol) by dropwise addition. After warming to RT the solutionwas concentrated to dryness at reduced pressure to afford the titlecompound as a light yellow solid in quantitative yield. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.48 (d, J=4.0 Hz, 1H) 8.09 (s, 1H) 7.98 (dd, J=8.9, 5.5Hz, 2H) 7.51 (d, J=7.9 Hz, 1H) 7.39 (t, J=8.9 Hz, 2H) 7.07-7.18 (m, 3H)3.55 (s, 6H) 3.28 (s, 3H) 2.82 (d, J=3.4 Hz, 3H) 2.10-2.23 (m, 1H)0.73-1.04 (m, 4H) 0.45 (s, 3H).

Example 18((4-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronicacid

Step 1:6-(N-(4-(Benzyloxy)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A stirred mixture of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(0.500 g, 1.24 mmol), (4-(benzyloxy)phenyl)boronic acid (0.567 g, 2.49mmol), copper(II) acetate (0.451 g, 2.49 mmol), and triethylamine (1.00mL, 7.12 mmol) in DCM (25 mL) was treated with 1.00 g of powdered 3angstrom molecular sieves. The resulting mixture was stirred at RT underair using a drying tube to exclude moisture. After 18 hours the mixturewas treated with an additional 250 mg portion of(4-(benzyloxy)phenyl)boronic acid and stirring at RT continued. Afteranother 8 hours the mixture was filtered through Celite and the filtrateconcentrated to dryness at reduced pressure. The black residue wassuspended in EtOAc and the undissolved solids removed by filtrationthrough Celite. The filtrate was concentrated to dryness at reducedpressure and the residue subjected to flash chromatography (silica gel,gradient elution from DCM to 1:1 DCM/EtOAc to give the title compound(0.403 g, 56%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.39-8.47 (m, 1H) 8.12-8.18 (m, 1H) 7.92-7.99 (m, 2H) 7.55 (d, J=8.9 Hz,2H) 7.28-7.46 (m, 7H) 7.13 (s, 1H) 7.03 (d, J=9.0 Hz, 2H) 5.09 (s, 2H)3.29 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.25-2.35 (m, 1H) 0.75-1.14 (m, 3H)0.32-0.58 (m, 1H). LCMS (m/z, ES⁺)=585 (M+H+).

Step 2:5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(4-hydroxyphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

A solution of6-(N-(4-(benzyloxy)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.174 g, 0.298 mmol) in 3:1 THF/EtOH (20 mL) was subjected tohydrogenation at 40 psi in the presence of 5% palladium on charcoal (20mg). After 3 hours the reaction vessel was purged with nitrogen,catalyst removed by filtration through Celite and the filtrateconcentrated to dryness at reduced pressure. The residue was trituratedwith DCM/hexane. The resulting solid was collected by filtration anddried in vacuo to afford the title compound (144 mg, 98%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.67 (br. s., 1H) 8.44(q, J=4.4 Hz, 1H) 8.13 (s, 1H) 7.97 (dd, J=8.9, 5.4 Hz, 2H) 7.46 (d,J=8.9 Hz, 2H) 7.40 (t, J=8.9 Hz, 2H) 7.12 (s, 1H) 6.77 (d, J=8.9 Hz, 2H)3.27 (s, 3H) 2.83 (d, J=4.6 Hz, 3H) 2.28-2.39 (m, 1H) 0.76-1.11 (m, 3H)0.47 (br. s., 1H). LCMS (m/z, ES⁺)=495 (M+H+).

Step 3:((4-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronicacid

A mixture of5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4-hydroxyphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide(85.0 mg, 0.172 mmol), potassium carbonate (0.119 g, 0.859 mmol), and2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.152 g, 0.688mmol) in MeCN (3 mL) in a sealed tube was heated to 65° C. withstirring. After 2 hours the mixture was cooled to RT, filtered to removesolids, and the filtrate concentrated to dryness at reduced pressure.The residue was subjected to RP-HPLC purification (C18, MeCN/water/0.1%formic acid) followed by lyophilization from MeCN/water to give thetitle compound (77 mg, 81%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.40-8.47 (m, 1H) 8.15 (s, 1H) 8.03 (s, 2H) 7.97 (dd, J=8.8, 5.4Hz, 2H) 7.53 (d, J=9.0 Hz, 2H) 7.40 (t, J=8.9 Hz, 2H) 7.12 (s, 1H) 6.90(d, J=9.1 Hz, 2H) 3.58 (s, 2H) 3.33 (s, 3H) 2.82 (d, J=4.5 Hz, 3H)2.24-2.38 (m, 1H) 0.76-1.10 (m, 3H) 0.47 (br. s., 1H). LCMS (m/z,ES⁺)=553 (M+H+).

Example 19((2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronicacid

Step 1:6-(N-(4-(Benzyloxy)-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(1.00 g, 2.49 mmol), (4-(benzyloxy)-3-chlorophenyl)boronic acid (1.31 g,4.97 mmol), copper(II) acetate (0.903 g, 4.97 mmol), and triethylamine(2.00 mL, 14.4 mmol) in anhydrous DCM (25 mL) was treated with powdered3 angstrom molecular sieves (2.00 g). The resulting mixture was stirredat RT under air using a drying tube to exclude moisture. After 18 hoursthe mixture was treated with an additional 1.00 g portion of(4-(benzyloxy)-3-chlorophenyl)boronic acid. After another 18 hours themixture was diluted with 15 mL of DCM and treated with 1.30 g of(4-(benzyloxy)-3-chlorophenyl)boronic acid, 0.900 g of copper(II)acetate, 2.00 g of 3 angstrom molecular sieves and 2 mL oftriethylamine. After 16 more hours the mixture was filtered throughCelite to remove solids and the filtrate concentrated to dryness atreduced pressure. The residue was suspended in EtOAc and the undissolvedsolids removed by filtration through Celite. The filtrate was washedwith water (2×), brine (1×), dried over sodium sulfate and concentratedto dryness at reduced pressure. The crude material was purified by flashchromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) followedby recrystallization from hexane/EtOAc to afford the title compound(0.83 g, 54%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.40-8.47 (m, 1H) 8.20 (s, 1H) 7.93-8.00 (m, 2H) 7.69 (d, J=2.6 Hz, 1H)7.52 (dd, J=8.9, 2.7 Hz, 1H) 7.30-7.48 (m, 7H) 7.25 (d, J=9.1 Hz, 1H)7.14 (s, 1H) 5.21 (s, 2H) 3.33 (s, 3H) 2.82 (d, J=4.6 Hz, 3H) 2.17-2.33(m, 1H) 0.75-1.09 (m, 3H) 0.42 (br. s., 1H). LCMS (m/z, ES⁺)=619, 621(M+H+).

Step 2:6-(N-(3-Chloro-4-hydroxyphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of6-(N-(4-(benzyloxy)-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.300 g, 0.485 mmol) in anhydrous DCM (12 mL) was cooled in an icewater bath and treated with 1M BCl₃/DCM (2.00 mL, 2.00 mmol). Afterstirring in the ice bath for 10 minutes the solution was allowed to warmto RT. This solution was then combined with the solution from ananalogous 50 mg scale reaction and poured into 50 mL of stirred icewater. The mixture was diluted with 50 mL of EtOAc, stirred vigorouslyfor several minutes and the phases separated. The EtOAc solution waswashed with water (2×), brine (1×), dried over sodium sulfate andconcentrated to dryness at reduced pressure. The crude material wassubjected to flash chromatography (silica gel, gradient from DCM to 1:1DCM/EtOAc) followed by recrystallization from hexane/EtOAc to afford thetitle compound (0.110 g, 37%) as a white powder. Impure fractions fromthe above chromatography were combined, concentrated, and subjected toRP-HPLC purification (C18, MeCN/water/0.1% formic acid) to afford anadditional portion of the title compound (0.107 g, 36%) for a totalyield of 73%. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.45 (s, 1H) 8.40-8.48(m, 1H) 8.18 (s, 1H) 7.90-8.01 (m, 2H) 7.61 (d, J=2.6 Hz, 1H) 7.34-7.45(m, 3H) 7.14 (s, 1H) 6.96 (d, J=8.8 Hz, 1H) 3.30 (s, 3H) 2.82 (d, J=4.6Hz, 3H) 2.20-2.34 (m, 1H) 0.77-1.09 (m, 3H) 0.43 (br. s., 1H). LCMS(m/z, ES⁺)=529 (M+H+).

Step 3:((2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronicacid

A mixture of6-(N-(3-chloro-4-hydroxyphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(65.0 mg, 0.123 mmol), potassium carbonate (85.0 mg, 0.614 mmol), and2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.109 g, 0.492mmol) in 4 mL of anhydrous MeCN in a sealed tube was heated to 65° C.with stirring. After 2 hours the mixture was cooled to RT, filtered toremove solids, and the filtrate concentrated to dryness at reducedpressure. The residue was subjected to RP-HPLC purification (C18,MeCN/water/0.1% formic acid) followed by lyophilization from MeCN/waterto afford the title compound (43 mg, 60%) as a white powder. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.40-8.47 (m, 1H) 8.20 (s, 1H) 8.05 (s, 2H) 7.97(dd, J=8.7, 5.5 Hz, 2H) 7.65 (d, J=2.5 Hz, 1H) 7.53 (dd, J=8.9, 2.6 Hz,1H) 7.40 (t, J=8.8 Hz, 2H) 7.14 (s, 1H) 7.00 (d, J=9.1 Hz, 1H) 3.73 (s,2H) 3.32 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.20-2.35 (m, 1H) 0.90 (br. s.,3H) 0.45 (br. s., 1H). LCMS (m/z, ES⁺)=587 (M+H+).

Example 205-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: Methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate

A mixture of methyl 5-fluoro-2-nitrobenzoate (2.138 g, 10.73 mmol),5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(4.0 g, 9.94 mmol) and K₂CO₃ (4.12 g, 29.8 mmol) inhexamethylphosphoramide (25 mL) in a seal tube was stirred at 60° C. for3 days. Cooled down to room temperature, the mixture was diluted withEtOAc and then filtered through a pad of Celite. The filtrate was washedwith water and brine and dried over Na₂SO₄. Concentrated under reducedpressure, the residue was purified by flashing chromatography on silicagel eluted with 0-50% EtOAc in hexane to give the product (3.2 g, 55%)as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=9.17Hz, 1H) 7.89 (dd, J=8.78, 5.27 Hz, 2H) 7.55 (d, J=9.37 Hz, 2H) 7.50 (dd,J=9.07, 2.63 Hz, 1H) 7.44 (d, J=2.73 Hz, 1H) 7.23 (t, J=8.68 Hz, 2H)5.81 (d, J=4.49 Hz, 1H) 3.91 (s, 3H) 3.35 (s, 3H) 3.02 (d, J=4.88 Hz,3H) 1.86-1.96 (m, 1H) 0.97-1.05 (m, 1H) 0.89 (br. s., 2H) 0.59 (br. s.,1H). LCMS (m/z, ES⁺)=582 (M+H+).

Step 2: Methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

Methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate(3.2 g, 5.50 mmol) was dissolved in methanol (50 mL), hydrogenation wascarried out under H₂ ((H₂ balloon) in the present of 10% Pd/C (0.586 g,0.550 mmol) at room temperature. The mixture was stirred for 6 hours, Itwas then filtered by pass through a pad of Celite. Concentrated underreduced pressure, it was rinsed twice with hexane to give the desiredproduct (3.0 g, 98%) as a yellow solid which was used for the next stepwithout further purification. LCMS (m/z, ES⁺)=552 (M+H+).

Step 3: Methyl2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

A suspension of methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate(1.6 g, 2.70 mmol) in acetonitrile (30 mL) and hydrogen bromide (25 mL,2.70 mmol) was treated with aqueous sodium nitrite (0.205 g, 2.97 mmol)at 0° C. and the mixture was stirred for 30 min, copper(I) bromide(0.464 g, 3.24 mmol) was added in portions at the same temperature. Itwas allowed to warm up to room temperature and then heated to 55° C.overnight. The mixture was cooled down to room temperature andpartitioned between EtOAc and water. The organic phase was washed withbrine, dried over Na₂SO₄. Concentrated under reduced pressure, theresidue was purified by flashing chromatography on silica gel elutedwith 0-50% EtOAc in hexane to give the product (0.92 g, 55%) as a whitefoam. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (q, J=4.23 Hz, 1H) 8.14 (s,1H) 7.97 (dd, J=8.78, 5.46 Hz, 2H) 7.80 (d, J=2.93 Hz, 1H) 7.75 (d,J=8.78 Hz, 1H) 7.50 (dd, J=8.88, 2.83 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H)7.22 (s, 1H) 3.84 (s, 3H) 3.44 (s, 3H) 2.84 (d, J=4.68 Hz, 3H) 2.05-2.15(m, 1H) 0.92-1.05 (br. s, 1H) 0.87 (br. s., 2H) 0.40 (br. s., 1H). LCMS(m/z, ES⁺)=617 (M+H+).

Step 4:6-(N-(4-Bromo-3-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LiBH₄ (1.593 mL, 3.19 mmol) solution (2M in THF) was added dropwise to asolution of methyl2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate(0.76 g, 1.062 mmol) in tetrahydrofuran (6.0 mL) and methanol (0.600 mL)at 0° C. under N₂. The mixture was stirred for 3 hours at the sametemperature. It was quenched with 1M NaOH and then partitioned betweenEtOAc and water. The aqueous layer was extracted with EtOAc (2×). Theorganic phase was washed with brine, dried over Na₂SO₄. It wasconcentrated to dryness to give the crude product (>99%) as tan foamwhich was used for the next step without further purification. LCMS(m/z, ES⁺)=587 (M+H+).

Step 5:6-(N-(4-Bromo-3-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Chloro(methoxy)methane (0.201 mL, 2.65 mmol) was added dropwise to asolution of6-(N-(4-bromo-3-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.724 g, 1.06 mmol) and DIEA (0.555 mL, 3.18 mmol) in tetrahydrofuran(10 mL) under N₂. The mixture was heated to 50° C. overnight. Cooleddown to room temperature and aqueous NaHCO₃ was added, the aqueous layerwas extracted with EtOAc (2×). The organic phase was washed with brine,dried over Na₂SO₄. The crude residue was purified by chromatography onsilica gel eluted with 0-50% EtOAC in hexane to give the product (0.65g, 97%) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (dd,J=8.78, 5.27 Hz, 2H) 7.64 (s, 1H) 7.57 (d, J=2.73 Hz, 1H) 7.50 (d,J=8.78 Hz, 1H) 7.47 (s, 1H) 7.18-7.26 (m, 3H) 5.79 (d, J=4.49 Hz, 1H)4.74 (s, 2H) 4.61 (s, 2H) 3.39 (s, 3H) 3.25 (s, 3H) 3.01 (d, J=4.88 Hz,3H) 2.08-2.18 (m, 1H) 0.75-1.14 (m, 3H) 0.58 (br. s., 1H). LCMS (m/z,ES⁺)=633 (M+H+).

Step 6:5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

A mixture of6-(N-(4-bromo-3-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(200 mg, 0.317 mmol), potassium acetate (124 mg, 1.267 mmol),bis(pinacolato)diboron (161 mg, 0.633 mmol) and PdCl₂(dppf)-CH₂Cl₂adduct (25.9 mg, 0.032 mmol) in 1,4-dioxane (3.0 ml) was maintained at90° C. in a seal tube under N₂ overnight. The mixture was cooled down toroom temperature, diluted with EtOAc, filtered through a pad of silicgel and Celite and then concentrated to dryness to give the crudeproduct as tan foam which was used for the next step without furtherpurification. LCMS (m/z, ES⁺)=679 (M+H+).

Step 7:(4-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-((methoxymethoxy)methyl)phenyl)boronicacid

The crude5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(3-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide(215 mg, 0.317 mmol) was dissolved in methanol (1.0 mL) andtetrahydrofuran (4.0 mL). HCl (4.0 mL, 4.00 mmol) was added followed byaddition of sodium periodate (542 mg, 2.54 mmol). The mixture wasstirred at room temperature overnight. It was partitioned between EtOAcand water. The aqueous layer was extracted with EtOAc (2×). The organicphase was washed with 10% aq. Na₂S₂O₃, brine, dried over Na₂SO₄.Concentrated under reduced pressure, the residue was purified byreversed phase HPLC (10-100 MeCN/H₂O with 0.05% TFA) to give product (54mg, 29%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.47 (q,J=4.36 Hz, 1H) 8.07 (s, 1H) 7.97 (dd, J=8.88, 5.37 Hz, 2H) 7.31-7.53 (m,5H) 7.14-7.20 (m, 1H) 4.65 (s, 2H) 4.59 (s, 2H) 3.37 (s, 2H) 3.24 (s,2H) 2.83 (d, J=4.68 Hz, 3H) 2.11-2.26 (m, 1H) 1.01 (br. s., 1H) 0.84(br. s., 2H) 0.52 (br. s., 1H). LCMS (m/z, ES⁺)=597 (M+H+).

Step 8:5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

HCl (1.0 mL, 1.000 mmol) was added to a solution of(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-((methoxymethoxy)methyl)phenyl)boronicacid (53 mg, 0.089 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.2mL). The mixture was heated to 70° C. under N₂ overnight. Cooled down toroom temperature, it was then evaporated to dry under reduced pressureto give the desired product (46 mg, 97%) as light-yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.20 (br. s., 1H) 8.49 (q, J=4.42 Hz,1H) 8.06 (s, 1H) 7.97 (dd, J=8.98, 5.46 Hz, 2H) 7.71 (d, J=8.19 Hz, 1H)7.48 (s, 1H) 7.35-7.44 (m, 3H) 7.19 (s, 1H) 4.96 (s, 2H) 3.42 (s, 3H)2.84 (d, J=4.68 Hz, 3H) 2.09-2.21 (m, 1H) 0.99 (br. s., 1H) 0.81 (d,J=5.27 Hz, 2H) 0.50 (br. s., 1H). LCMS (m/z, ES⁺)=535 (M+H+).

Example 214-(N-(2-(4-Chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-cyanophenyl)boronicacid

Step 1:2-(4-Chlorophenyl)-6-(N-(3-cyano-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide

A mixture of 5-fluoro-2-nitrobenzonitrile (0.656 mL, 5.73 mmol),2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(2.0 g, 4.77 mmol) and K₂CO₃ (1.980 g, 14.32 mmol) in1,2-dimethoxyethane (20 mL) and water (5.0 mL) in a seal tube was heatedto 80° C. overnight. Cooled down to room temperature, it was dilutedwith EtOAc. The mixture was washed with water and brine, dried overNa₂SO₄. It was concentrated to dryness to give the crude product (>99%)as yellow solid which was used for the next step without furtherpurification. LCMS (m/z, ES⁺)=565 (M+H+).

Step 2:6-(N-(4-Amino-3-cyanophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide

A solution of Na₂S₂O₄ (4.98 g, 28.6 mmol) in water (50 mL) was addeddropwise to a solution of2-(4-chlorophenyl)-6-(N-(3-cyano-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide(2.70 g, 4.77 mmol) in THF at room temperature under N₂. The mixture wasstirred overnight. More water was added and then extracted with EtOAc.The combined extracts were washed with brine, dried over Na₂SO₄.Concentrated under reduced pressure, the crude residue was purified bychromatography on silica gel eluted with 0-15% EtOAc in DCM to give theproduct (2.3 g, 83%) as a white solid. LCMS (m/z, ES⁺)=535 (M+H+).

Step 3:6-(N-(4-Bromo-3-cyanophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide

tBuNO₂ (0.611 ml, 5.14 mmol) was added dropwise to a solution of CuBr₂(0.918 g, 4.11 mmol) in acetonitrile (5 mL). The mixture was heated to50° C. for 10 min and then a suspension of6-(N-(4-amino-3-cyanophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide(1.1 g, 2.056 mmol) in acetonitrile (25 mL) was added in portions toabove mixture. It was stirred for 30 min at 50° C. and then cooled downto room temperature. It was quenched with ice-cooled HCl (1 N) and thenextracted with EtOAc. The combined extracts were washed with 10% Na₂S₂O₃and brine, dried over Na₂SO₄, Concentrated under reduced pressure, theresidue was purified by flashing chromatography on silica gel elutedwith 0-5% EtOAc in DCM to give the product (0.64 g, 52%) as alight-yellow foam. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84 (d, J=8.59Hz, 2H) 7.58-7.64 (m, 3H) 7.47-7.53 (m, 4H) 5.80 (d, J=4.29 Hz, 1H) 3.28(s, 3H) 3.03 (d, J=4.88 Hz, 3H) 1.91-2.00 (m, 1H) 0.72-1.11 (m, 3H) 0.55(br. s., 1H). LCMS (m/z, ES⁺)=600 (M+H+).

Step 4:2-(4-Chlorophenyl)-6-(N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide

A mixture of6-(N-(4-bromo-3-cyanophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide(150 mg, 0.250 mmol), potassium acetate (98 mg, 1.002 mmol),bis(pinacolato)diboron (127 mg, 0.501 mmol) and PdCl₂(dppf)-CH₂Cl₂adduct (20.5 mg, 0.025 mmol) in 1,4-dioxane (3 ml) was maintained at 90°C. in a seal tube under N2 for 3 hours. LCMS (UV 254) showed 47% ofdesired product, 53% of the corresponding boronic acid (generated on LCprobably?). The mixture was cooled down to room temperature, dilutedwith EtOAc, filtered through a pad of silic gel and Celite and thenconcentrated to dryness to give the crude product (>99%) as light-yellowfoam which was used for the next step without further purification. LCMS(m/z, ES⁺)=646 (M+H+).

Step 5:(4-(N-(2-(4-Chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-cyanophenyl)boronicacid

The crude2-(4-chlorophenyl)-6-(N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide(162 mg, 0.251 mmol) was dissolved in tetrahydrofuran (6.0 mL). HCl(3.01 mL, 1.505 mmol) was added followed by addition of sodium periodate(429 mg, 2.006 mmol). The mixture was stirred at room temperatureovernight. It was partitioned between EtOAc and water. The aqueous layerwas extracted with EtOAc (2×). The organic phase was washed with 10% aq.Na₂S₂O₃ and brine, dried over Na₂SO₄. Concentrated under reducedpressure, the residue was purified by reversed phase HPLC (10-100MeCN/H₂O with 0.05% TFA) to give product (88 mg, 62%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.54-8.74 (br.s., 1H) 8.51 (q, J=4.49Hz, 2H) 8.13 (s, 1H) 7.93 (d, J=8.78 Hz, 2H) 7.74-7.79 (m, 2H) 7.58-7.67(m, 3H) 7.22 (s, 1H) 3.47 (s, 3H) 2.84 (d, J=4.68 Hz, 3H) 2.03-2.14 (m,1H) 0.99 (br. s., 1H) 0.85 (br. s., 2H) 0.45 (br. s., 1H). LCMS (m/z,ES⁺)=564 (M+H+).

Example 225-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide

Step 1:5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamideTo the mixture of6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(2.5 g, 4.48 mmol) and DABAL-Me₃ (1.366 g, 5.38 mmol) in dryTetrahydrofuran (10 mL) under nitrogen atmosphere was added Pd₂(dba)₃(0.041 g, 0.045 mmol) and Xantphos (0.052 g, 0.090 mmol) and thereaction was refluxed at 100° C. for 0.5 h. Reaction mixture wasfiltered through Celite and washed with methanol (50 mL). Afterevaporation of the solvent, the crude was redissolved in DCM and washedwith water. DCM was dried over anhydrous Na₂SO₄ and evaporated to givethe title compound as a yellow solid in 82% yield. ¹H NMR (400 MHz,DMSO-d₆) ppm: 8.02 (d, J=9.2 Hz, 1H), 7.86-7.93 (m, 2H), 7.55 (d, J=1.8Hz, 2H), 7.17-7.27 (m, 4H), 5.80 (d, J=4.5 Hz, 1H), 3.22-3.44 (m, 3H),3.02 (d, J=4.9 Hz, 3H), 2.47-2.66 (m, 3H), 1.88-2.11 (m, 1H), 1.03 (br.s., 1H), 0.89 (d, J=7.2 Hz, 2H), 0.62 (br. s., 1H). LCMS (m/z, ES⁺)=538(M+H+).

Step 2:6-(N-(4-Amino-3-methylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamide(2.0 g, 3.72 mmol) in Ethanol (10 mL) and THF (2 mL), Pd/C (0.396 g) wasadded and subjected to hydrogenation at RT for 12 h. The reactionmixture was filtered through Celite. The solvent was evaporated underreduced pressure to afford the title compound in 86% yield. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 7.85-7.95 (m, 1H), 7.67-7.73 (m, 1H), 7.37-7.42 (m,1H), 7.11-7.26 (m, 1H), 6.59-6.68 (m, 1H), 5.86 (br. s., 1H), 3.18 (s,1H), 2.99 (s, 2H), 2.10-2.17 (m, 1H), 1.37-1.51 (m, 1H), 1.08-1.19 (m,1H), 0.91-1.06 (m, 1H), 0.45-0.92 (m, 1H). LCMS (m/z, ES⁺)=508 (M+H+).

Step 3:5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(4-iodo-3-methylphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

6-(N-(4-Amino-3-methylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(1.0 g, 1.97 mmol) was added to p-TsOH (1.12 g, 5.91 mmol) in t-butanol(2 mL) at 5° C. and stirred for 10 min. Then a mixture of sodium nitrite(0.272 g, 3.94 mmol) and KI (0.818 g, 4.93 mmol) in water (1 mL) wasadded to the reaction mixture. Stirred for 15 min at same temperature,brought to RT and heated at 60° C. for 15 min. Water, sodium bicarbonatesolution and sodium thiosulfate solutions (20 mL) were addedsuccessively. The resulting precipitate was filtered and dried to givethe title compound as a yellow solid in 83% yield. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 7.84-7.97 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.58-7.67 (m,1H), 7.47 (s, 1H), 7.26 (br. s., 1H), 7.22 (t, J=8.6 Hz, 2H), 6.92-7.05(m, 1H), 5.79 (br. s., 1H), 3.25 (s, 3H), 3.02 (d, J=4.9 Hz, 3H), 2.39(s, 3H), 0.96 (d, J=6.8 Hz, 2H), 0.85 (br. s., 2H), 0.61 (br. s., 1H).LCMS (m/z, ES⁺)=618 (M+H+).

Step 4:5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide

To bis(pinacolato)diboron (103 mg, 0.404 mmol),[bis(diphenylphosphino)ferrocene]dichloropalladium(III) complex (33.0mg, 0.040 mmol) and potassium acetate (39.7 mg, 0.404 mmol) under anitrogen atmosphere was added5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(4-iodo-3-methylphenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide(50 mg, 0.081 mmol) and 1,4-dioxane (2 mL) and stirred for 12 h at 80°C. The product and de-iodo product were formed in 80:20 ratio. Themixture was diluted with water and extracted with ethyl acetate (20 mL).Ethyl acetate solution was dried over anhydrous Na₂SO₄ and evaporatedunder reduced pressure. The crude was purified by RP-HPLC(ACN/Water/0.1% formic acid) to provide the title compound in 5% yield.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.44-8.56 (m, 1H), 7.90-8.05 (m, 3H),7.60 (d, J=8.0 Hz, 1H), 7.41 (t, J=8.9 Hz, 2H), 7.12-7.25 (m, 3H), 6.77(s, OH), 2.84 (d, J=4.5 Hz, 3H), 2.42 (s, 3H), 1.28 (s, 12H), 0.98 (br.s., 1H), 0.79 (br. s., 2H), 0.51 (br. s., 1H). LCMS (m/z, ES⁺)=619(M+H+).

Example 23(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronicacid

Step 1:6-(N-(3-Chloro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of6-(N-(3-chloro-4-vinylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(200 mg, 0.371 mmol) in THF (2 mL) was added to a stirred solution ofbis(1,5-cyclooctadiene)diiridium(I) dichloride (6.2 mg, 0.0091 mmol) anddiphenylphosphinobutane (7.9 mg, 0.019 mmol) in THF (2 mL) undernitrogen. After 10 min, pinacolborane (1 M in THF) (1.1 mL, 1.11 mmol)was added and the mixture was stirred at room temperature for 3 days.The solvent was evaporated and the residue was subjected to silica gelchromatography with dichloromethane:methanol to give 158 mg of a mixturecontaining 60% of6-(N-(3-Chloro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide.This material was taken to the next step without further purification.LCMS (m/z, ES⁺)=667 (M+H+).

Step 2:(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronicacid

Sodium periodate (722 mg, 3.37 mmol) and 1N aqueous HCl (2.70 mL, 2.70mmol) were added to a cold (0° C.) solution of6-(N-(3-chloro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(150 mg, 0.225 mmol) in THF (3 mL). The mixture was stirred at 0° C. for10 min and then warmed to room temperature and stirred for 1 hour. Thereaction mixture was diluted with ethyl acetate. The organic layer wasseparated, washed with 5% aqueous sodium thiosulfate and brine and driedover sodium sulfate. The solvent was evaporated and the residue wassubjected to reverse phase HPLC (C18, acetonitrile:water with 0.1%formic acid) to give 33 mg (25%) of the title compound as a whitepowder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.41-8.51 (m, 1H) 8.14 (s, 1H)7.92-8.02 (m, 2H) 7.59 (s, 2H) 7.46-7.51 (m, 1H) 7.35-7.44 (m, 3H)7.29-7.35 (m, 1H) 7.17 (s, 1H) 3.37 (s, 3H) 2.79-2.87 (m, 3H) 2.62-2.74(m, 2H) 2.11-2.24 (m, 1H) 0.93-1.09 (m, 1H) 0.75-0.93 (m, 4H) 0.46 (m,1H). LCMS (m/z, ES⁺)=585 (M+H+).

Example 245-Cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: Methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluoro-2-nitrobenzoate

A mixture of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide(1.850 g, 4.60 mmol), methyl 3,5-difluoro-2-nitrobenzoate (1.996 g, 9.19mmol) and Na₂CO₃ (1.462 g, 13.79 mmol) in hexamethylphosphoramide (25mL) was stirred overnight at room temperature. The mixture was dilutedwith EtOAc and filtered through a pad of Celite®. The filtrate waswashed with brine, dried over Na₂SO₄, concentrated and purified bysilica gel chromatography (0-35% EtOAc in hexanes) to give methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluoro-2-nitrobenzoate(1.61 g, 58% yield) as yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 0.62 (br. s., 1H), 0.79-0.95 (m, 2H), 0.96-1.11 (m, 1H), 1.84-1.97(m, 1H), 3.01 (d, J=5.0 Hz, 3H), 3.31-3.36 (m, 3H), 3.87 (s, 3H), 5.82(d, J=4.6 Hz, 1H), 7.22 (t, J=8.6 Hz, 2H), 7.37-7.44 (m, 1H), 7.50-7.54(m, 2H), 7.56 (s, 1H), 7.83-7.92 (m, 2H). LCMS (m/z, ES⁺)=600.2 (M+H+).

Step 2: Methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate

A suspension of methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluoro-2-nitrobenzoate(810 mg, 1.351 mmol) and Pd/C (10% wt, 144 mg, 0.135 mmol) was stirredunder hydrogen (1 atm) in THF (10.0 mL) and MeOH (5.0 mL) overnight. Themixture was filtered through 45 um disc and washed with EtOAc. Thefiltrate was concentrated and purified by silica gel chromatography(0-50% EtOAc in hexanes) to give methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate(601 mg, 78% yield) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm0.81-1.11 (m, 3H), 2.14-2.26 (m, 1H), 2.91-3.03 (m, 3H), 3.19 (s, 3H),3.86 (s, 3H), 5.80 (d, J=4.5 Hz, 1H), 5.88 (br. s., 2H), 7.15-7.25 (m,2H), 7.40 (dd, J=12.1, 2.5 Hz, 1H), 7.44 (s, 1H), 7.70 (s, 1H), 7.80(dd, J=2.4, 1.5 Hz, 1H), 7.84-7.94 (m, 2H). LCMS (m/z, ES+)=570.3(M+H+).

Step 3: Methyl2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate

A solution of methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate(601 mg, 1.055 mmol) in acetonitrile (6 mL) and conc. HBr (6 mL, 48% aq)was cooled in an ice-water bath and then treated with a solution ofsodium nitrite (95 mg, 1.372 mmol) in water (1 mL). After 15 min,copper(I) bromide (182 mg, 1.266 mmol) was added to the mixture. Themixture was then heated to 50° C. After 30 min, the solution was cooledto room temperature and diluted with EtOAc. Sodium bisulfate (15 mL, 5%aq) and saturated aqueous NaHCO₃ solution (20 mL) were added to thesolution. The organic phase was separated and washed by brine (40 mL),dried over Na₂SO₄, concentrated and then purified by silica gelchromatography (0-35% EtOAc in hexanes) to give methyl2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate(430 mg, 64% yield) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm0.55 (br. s., 1H), 0.75-0.93 (m, 2H), 0.97 (d, J=6.6 Hz, 1H), 1.88-2.04(m, 1H), 3.01 (d, J=4.9 Hz, 3H), 3.28 (s, 3H), 3.91 (s, 3H), 5.72-5.85(m, 1H), 7.21 (t, J=8.6 Hz, 2H), 7.33 (dd, J=10.0, 2.8 Hz, 1H), 7.49(dd, J=2.8, 1.3 Hz, 1H), 7.52 (s, 1H), 7.58 (s, 1H), 7.85-7.92 (m, 2H).LCMS (m/z, ES+)=633, 635 (M+H+).

Step 4:6-(N-(4-Bromo-3-fluoro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of LiBH₄ (1.018 mL, 2M) in THF was added dropwise to asolution of methyl2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate(430 mg, 0.679 mmol) in MeOH (0.5 mL) and THF (5.0 mL) at 0° C. After0.5 h, citric acid (4.0 mL, 5% wt) was added to the mixture. The organicsolvent was then removed under reduced pressure. The residue was dilutedwith DCM (10 mL) and washed with saturated aqueous NaHCO₃, brine, driedover Na₂SO₄, filtered and concentrated to give6-(N-(4-bromo-3-fluoro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(400 mg, 97% yield) as white solid. The crude was used for next stepwithout more purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57(br. s., 1H), 0.71-0.88 (m, 2H), 0.93-1.06 (m, 1H), 1.96-2.02 (m, 1H),2.63 (t, J=6.1 Hz, 1H), 2.96 (d, J=4.8 Hz, 3H), 3.25 (s, 3H), 4.67 (d,J=5.6 Hz, 2H), 5.96 (d, J=4.8 Hz, 1H), 7.08-7.21 (m, 3H), 7.31 (s, 1H),7.42 (s, 1H), 7.56 (s, 1H), 7.82 (dd, J=8.7, 5.3 Hz, 2H). LCMS (m/z,ES+)=605, 607 (M+H+).

Step 5:6-(N-(4-Bromo-3-fluoro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of6-(N-(4-bromo-3-fluoro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(350 mg, 0.578 mmol), DIPEA (0.303 mL, 1.734 mmol) and MOM-Cl (0.110 mL,1.445 mmol) in THF (3.0 mL) was stirred at 50° C. in a sealed tube.After 23 hours, the solution was concentrated and purified by silica gelchromatography (0-40% EtOAc in hexanes) to give6-(N-(4-bromo-3-fluoro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(303 mg, 70% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.59 (br. s.,1H), 0.74-0.94 (m, 2H), 0.94-1.10 (m, 1H), 1.99-2.12 (m, 1H), 3.00 (d,J=4.9 Hz, 3H), 3.27 (s, 3H), 3.37 (s, 3H), 4.61 (s, 2H), 4.71 (s, 2H),5.85 (d, J=4.6 Hz, 1H), 7.13 (dd, J=10.0, 2.7 Hz, 1H), 7.17-7.25 (m,2H), 7.33 (d, J=1.5 Hz, 1H), 7.48 (s, 1H), 7.58 (s, 1H), 7.83-7.92 (m,2H). LCMS (m/z, ES+)=649, 651 (M+H+).

Step 6:5-Cyclopropyl-6-(N-(3-fluoro-5-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of6-(N-(4-bromo-3-fluoro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(300 mg, 0.462 mmol), bis(pinacolato)diboron (293 mg, 1.155 mmol),potassium acetate (181 mg, 1.848 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct(37.7 mg, 0.046 mmol) in 1,4-dioxane (4.0 mL) was stirred under N₂ at90° C. in a sealed tube overnight. The mixture was cooled to roomtemperature, diluted with EtOAc, filtered through a pad of silica geland Celite® and then concentrated to dryness to give the crude product(306 mg) (68% of the title compound, 26% of deborylation by-product)which was used for the next step without further purification. LCMS(m/z, ES+)=697 (M+H+).

Step 7:5-Cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Aqueous hydrochloric acid (4 mL, 1 N) was added to a solution of5-cyclopropyl-6-(N-(3-fluoro-5-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(306 mg) in THF (4.0 mL) and MeOH (0.8 mL). The mixture was heated to70° C. under N₂ overnight. The mixture was cooled to room temperatureand the organic solvent was removed under reduced pressure. The crudewas diluted with EtOAc, washed with brine, dried over Na₂SO₄, filteredand concentrated to dryness. MeOH (6 mL) was then added to the crude andstirred for 15 min. A white solid was formed which was filtered to give170 mg crude product (90% purity). 50 mg crude product was purified bysilica gel chromatography (0-100% EtOAc in DCM, then 0-10% MeOH in DCM)to give5-cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(17 mg, 6.24% yield). Another 120 mg crude product was washed with MeOHand dried to give5-cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(106 mg, 36.6% yield). ¹H NMR (400 MHz, DMSO-d6) 8 ppm 0.50 (br. s.,1H), 0.81 (br. s., 2H), 0.97 (br. s., 1H), 2.06 (br. s., 1H), 2.84 (d,J=4.3 Hz, 3H), 3.48 (s, 3H), 4.95 (s, 2H), 7.02 (d, J=9.9 Hz, 1H), 7.20(d, J=7.9 Hz, 2H), 7.41 (t, J=8.8 Hz, 2H), 7.97 (dd, J=8.5, 5.6 Hz, 2H),8.04 (s, 1H), 8.49 (d, J=4.5 Hz, 1H), 9.28 (s, 1H). LCMS (m/z, ES+)=553(M+H+).

Example 256-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-4-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1:6-(N-(3-Chloro-4-(3-hydroxyprop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(327 mg, 0.552 mmol), allyl alcohol (0.475 mL, 6.9 mmol), palladium(II)acetate (29 mg, 0.132 mmol), 1,3-bis(diphenylphosphino)propane (108 mg,0.26 mmol) and triethylamine (0.7 mL, 4.9 mmol) in DMSO (2 mL) and1-butyl-3-methylimidazolium tetrafluoroborate (2 mL) was heated at 135°C. in a sealed tube for 59 hours. The reaction mixture was diluted withethyl acetate and filtered through Celite. The filtrate was washed withwater and brine, dried over sodium sulfate and concentrated.Chromatography on silica gel (hexane: ethyl acetate) gave 75 mg (24%) of6-(N-(3-chloro-4-(3-hydroxyprop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide.¹H NMR (400 MHz, chloroform-d) δ ppm 7.84-7.97 (m, 2H) 7.60 (s, 1H) 7.48(s, 1H) 7.37-7.41 (m, 1H) 7.29-7.32 (m, 1H) 7.28 (s, 1H) 7.16-7.24 (m,3H) 5.77-5.97 (m, 1H) 5.51-5.63 (m, 1H) 5.17 (s, 1H) 4.34-4.46 (m, 2H)3.28 (s, 3H) 3.00 (d, J=4.88 Hz, 3H) 2.1 (m, 1H) 0.99-1.10 (m, 1H)0.77-0.93 (m, 2H) 0.48-0.73 (m, 1H).). LCMS (m/z, ES⁺)=569 (M+H+).

Step 2:6-(N-(3-Chloro-4-(3-(methoxymethoxy)prop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Methyl chloromethyl ether (0.024 mL, 0.321 mmol) was added to a mixtureof6-(N-(3-chloro-4-(3-hydroxyprop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(83 mg, 0.146 mmol) and DIEA (0.076 mL, 0.438 mmol) in dichloromethane(2 mL). The mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was diluted with dichloromethane and washed with waterand brine, dried over sodium sulfate and concentrated to give6-(N-(3-chloro-4-(3-(methoxymethoxy)prop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a white foam (76 mg, 85%). ¹H NMR (400 MHz, chloroform-d) δ ppm 7.89(dd, J=8.78, 5.27 Hz, 2H) 7.60 (s, 1H) 7.48 (s, 1H) 7.38 (d, J=2.15 Hz,1H) 7.26-7.31 (m, 1H) 7.16-7.24 (m, 2H) 5.77-5.94 (m, 1H) 5.56 (s, 1H)5.31 (s, 1H) 5.22 (s, 1H) 4.65 (s, 2H) 4.34 (s, 2H) 3.33 (s, 3H) 3.27(s, 3H) 3.00 (d, J=4.88 Hz, 3H) 1.87-2.29 (m, 1H) 0.14-1.47 (m, 4H).LCMS (m/z, ES⁺)=613 (M+H+).

Step 3:6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-4-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Bis(1,5-cyclooctadiene)diiridium(I) dichloride (2.054 mg, 3.06 μmol) anddiphenylphosphinobutane (2.61 mg, 6.12 μmol) were dissolved in THF (1mL) under nitrogen. A solution of6-(N-(3-chloro-4-(3-(methoxymethoxy)prop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(75 mg, 0.122 mmol) in THF (1 mL) was added. After stirring for 10 min,pinacolborane (1M in THF) (0.367 mL, 0.367 mmol) was added and themixture was stirred at room temperature for 18 hours. The solvent wasevaporated and the residue was subjected to silica gel chromatographywith hexane:EtOAc to give a mixture containing 47% of the titlecompound. To this material was added THF (1 mL) and 1N aqueous HCl (1mL, 1.00 mmol). After heating at 70° C. for 18 hours, the solvent wasevaporated and the residue was purified by reverse phase HPLC (C18,acetonitrile:water with 0.1% formic acid) to give the title compound(7.8 mg, 10.2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.71(s, 1H) 8.41-8.50 (m, 1H) 8.11 (s, 1H) 7.90-8.01 (m, 2H) 7.32-7.52 (m,5H) 7.17 (s, 1H) 4.12-4.27 (m, 1H) 3.62-3.83 (m, 2H) 3.39 (s, 3H) 2.82(d, J=4.69 Hz, 3H) 2.09-2.22 (m, 1H) 1.17-1.32 (m, 1H) 0.92-1.06 (m, 2H)0.72-0.90 (m, 2H) 0.46 (m, 1H). LCMS (m/z, ES⁺)=597 (M+H+).

Example 26(3-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronicacid

Step 1: Ethyl6-((3-bromophenyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate

A mixture of ethyl6-amino-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (1.00g, 2.95 mmol), (3-bromophenyl)boronic acid (1.184 g, 5.89 mmol),copper(II) acetate (0.803 g, 4.42 mmol), triethylamine (1.232 mL, 8.84mmol) and 4 A molecular sieves (2 g) was stirred at room temperature for24 hours. The reaction mixture was diluted with EtOAc and filteredthrough Celite. The solvent was evaporated and the residue was purifiedby chromatography on silica gel (hexane:EtOAc) to give ethyl6-((3-bromophenyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate(740 mg, 51%). LCMS (m/z, ES⁺)=494, 496 (M+H, M+2).

Step 2: Ethyl6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate

A solution of lithium bis(trimethylsilyl)amide (1 M in THF) (1.93 mL,1.93 mmol) was added dropwise to a solution of ethyl6-((3-bromophenyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate(734 mg, 1.48 mmol) in THF (10 mL) at −78° C. The mixture was stirredfor 45 minutes and then a solution of methanesulfonyl chloride (0.463mL, 5.94 mmol) in THF (1.5 mL) was added at −78° C. After completeaddition the reaction mixture was allowed to warm to room temperatureovernight. Water and EtOAc were added. The organic layer was washed withwater and brine, dried over sodium sulfate and concentrated. The residuewas purified by silica gel chromatography (hexane:EtOAc) to give ethyl6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate(318 mg, 37%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.20(s, 1H) 8.03-8.13 (m, 2H) 7.62-7.66 (m, 1H) 7.59 (s, 1H) 7.43 (s, 4H)7.30-7.39 (m, 1H) 4.26-4.41 (m, 2H) 3.42 (s, 3H) 2.12-2.26 (m, 1H)1.28-1.37 (m, 3H) 0.71-1.14 (m, 4H) 0.41 (m, 1H). %). LCMS (m/z,ES⁺)=572, 574 (M+H, M+2).

Step 3:6-(N-(3-Bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylicacid

Lithium hydroxide monohydrate (68.5 mg, 1.630 mmol) was added to asuspension of ethyl6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate(311 mg, 0.543 mmol) in THF:MeOH:water/3:1:1 (10 mL). The mixture wasstirred at room temperature overnight. The mixture was acidified with 2Naqueous HCl and the volatile solvents were evaporated. The residue waspartitioned between EtOAc and water. The organic layers were washed withbrine, dried over sodium sulfate and concentrated to give6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylicacid (309 mg, quantitative) as a yellow solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.01-8.13 (m, 2H) 7.77 (s, 1H) 7.66 (s, 1H) 7.54 (t,J=1.95 Hz, 1H) 7.39 (dd, J=8.21, 1.37 Hz, 1H) 7.30-7.36 (m, 1H)7.17-7.26 (m, 3H) 3.27 (s, 3H) 2.11 (s, 1H) 0.74-1.18 (m, 3H) 0.48-0.74(m, 1H). LCMS (m/z, ES⁺)=544, 546 (M+H, M+2).

Step 4:6-(N-(3-Bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

HATU (237 mg, 0.624 mmol) was added to a solution of6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylicacid (283 mg, 0.520 mmol), methylamine hydrochloride (70.2 mg, 1.040mmol) and DIEA (0.318 mL, 1.819 mmol) in DMF (2 mL) at room temperature.The mixture was stirred for one hour. The reaction mixture was dilutedwith EtOAc. The organic layer was washed with water and brine, driedover sodium sulfate and concentrated. The residue was purified by silicagel chromatography (hexane:ethyl acetate) to give6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(230 mg, 79%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.47 (s, 1H) 8.12 (s, 1H) 7.96 (dd, J=8.98, 5.47 Hz, 2H) 7.60 (t, J=2.05Hz, 1H) 7.27-7.54 (m, 5H) 7.18 (s, 1H) 3.41 (s, 3H) 2.82 (d, J=4.69 Hz,3H) 2.07-2.22 (m, 1H) 0.65-1.09 (m, 3H) 0.41 (m, 1H). LCMS (m/z,ES⁺)=557, 559 (M+H, M+2).

Step 5:5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-vinylphenyl)methylsulfonamido)benzofuran-3-carboxamide

A mixture of6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(221 mg, 0.396 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(0.134 mL, 0.793 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (32.4 mg, 0.040 mmol) and sodium carbonate (126 mg,1.189 mmol) in dioxane:water/4:1 (5 mL) was heated in a microwavereactor at 130° C. for 30 minutes. The reaction mixture was diluted withEtOAc and filtered through Celite. The solvent was evaporated and theresidue was purified by silica gel chromatography (hexane:EtOAc) to give5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-vinylphenyl)methylsulfonamido)benzofuran-3-carboxamide(171 mg, 85% purity) as a sticky off-white foam. LCMS (m/z, ES⁺)=505(M+H+). This material was taken to the next step without furtherpurification.

Step 6:5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)benzofuran-3-carboxamide

Bis(1,5-cyclooctadiene)diiridium(I) dichloride (5.29 mg, 7.88 μmol) anddiphenylphosphinobutane (6.72 mg, 0.016 mmol) were dissolved in THF (2mL) under nitrogen. A suspension of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-vinylphenyl)methylsulfonamido)benzofuran-3-carboxamide(159 mg, 0.315 mmol) in THF (2 mL) was added. After stirring for 10 min,pinacolborane (1M in THF) (0.95 mL, 0.945 mmol) was added and themixture was stirred at room temperature for 2 hours. The solvent wasevaporated and the residue was subjected to silica gel chromatography(dichloromethan:methanol) to give5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)benzofuran-3-carboxamide(75 mg, 38%, 82% purity. This material was taken to next step withoutfurther purification. LCMS (m/z, ES⁺)=633 (M+H+).

Step 7:(3-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronicacid

Sodium periodate (380 mg, 1.78 mmol) and 1N aqueous HCl (1.5 mL, 1.5mmol) were added to a cold (0° C.) solution of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)benzofuran-3-carboxamide(75 mg, 0.119 mmol) in THF (3 mL). The mixture was stirred at 0° C. for10 min then warmed to room temperature. After one hour, the reactionmixture was diluted with EtOAc and the organic layer was separated andwashed with 5% aqueous sodium thiosulfate and brine and dried oversodium sulfate. The solvent was evaporated and the residue was subjectedto reverse phase HPLC (C18, acetonitrile:water with 0.1% formic acid) togive the title compound (22 mg, 34%) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) d ppm 8.42-8.53 (m, 1H) 8.06-8.13 (m, 1H) 7.92-8.02 (m, 2H)7.55 (s, 2H) 7.34-7.46 (m, 3H) 7.24-7.30 (m, 2H) 7.14-7.18 (m, 1H)7.04-7.11 (m, 1H) 2.83 (d, J=4.68 Hz, 3H) 2.58-2.67 (m, 2H) 2.48-2.55(m, 3H) 2.15-2.31 (m, 1H) 0.94-1.11 (m, 1H) 0.75-0.94 (m, 4H) 0.47 (m,1H). LCMS (m/z, ES⁺)=551 (M+H+).

Example 276-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1:6-(N-(3-Chloro-4-vinylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(1.00 g, 1.69 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (138 mg, 0.169 mmol),sodium carbonate (537 mg, 5.07 mmol) and vinylboronic acid pinacol ester(0.573 mL, 3.38 mmol) in a 9:1 mixture of 1,4-dioxane and water (20 mL)was degassed and heated at 80° for 16 h. The mixture was cooled to rt,then poured into water and extracted with EtOAc (3×). The combinedorganic layers were washed with brine (1×), dried over sodium sulfateand concentrated under reduced pressure. The light brown oily residuewas purified by flash chromatography (silica gel, gradient of 0 to 50%EtOAc in hexanes) to afford the title compound (821 mg, 90%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (q, 1H), 8.08-8.14 (m, 1H),7.92-8.02 (m, 2H), 7.70-7.76 (m, 1H), 7.34-7.47 (m, 4H), 7.17-7.24 (m,1H), 6.96 (dd, 1H), 5.87 (d, 1H), 5.44 (d, 1H), 3.39-3.47 (m, 3H), 2.83(d, 3H), 2.04-2.16 (m, 1H), 0.73-1.03 (m, 3H), 0.36-0.55 (m, 1H). LCMS(m/z, ES⁺)=539 (M+H+).

Step 2:6-(N-(3-Chloro-4-formylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A suspension of6-(N-(3-chloro-4-vinylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(890 mg, 1.65 mmol) in 1:1 THF/water (36 mL) was treated with a solutionof osmium tetroxide (2.5% in t-butanol, 0.415 mL, 0.033 mmol) andstirred for a few minutes. The resulting solution was treated withsodium periodate (883 mg, 4.13 mmol) and the reaction mixture wasstirred for 16 h at rt. The reaction mixture was diluted with EtOAc andwashed with 1:1 water/brine (1×), then brine (1×). The organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane, filtered and the filtrate waspurified by flash chromatography (silica gel, gradient of 0 to 50% EtOAcin hexanes) to afford the title compound (0.45 g, 50%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) ppm 10.23 (s, 1H), 8.45-8.53 (m, 1H), 8.04 (s,1H), 7.94-8.01 (m, 2H), 7.86 (d, 1H), 7.35-7.46 (m, 3H), 7.31 (dd, 1H),7.24-7.29 (m, 1H), 3.57 (s, 3H), 2.84 (d, 3H), 1.89-1.98 (m, 1H),0.68-1.02 (m, 3H), 0.42-0.58 (m, 1H). LCMS (m/z, ES⁺)=541 (M+H+).

Step 3:6-(N-(3-Chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of6-(N-(3-chloro-4-formylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.25 g, 0.46 mmol) in THF (10 mL) was cooled to 0° and treated withvinylmagnesium bromide (1 M in THF, 1.02 mL). The reaction mixture wasallowed to warm to rt as the bath melted. After 5 h, the reactionmixture was poured into saturated ammonium chloride and extracted withEtOAc (2×). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure. Purification by flashchromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes)afforded the title compound (188 mg, 72%) as a white foam. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.45 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H),7.36-7.56 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.71 (d, 1H), 5.35 (t,1H), 5.22 (dt, 1H), 5.04-5.11 (m, 1H), 3.40 (s, 3H), 2.83 (d, 3H),2.09-2.19 (m, 1H), 0.76-1.07 (m, 3H), 0.39-0.54 (m, 1H). LCMS (m/z,ES⁺)=569 (M+H+).

Step 4:6-(N-(3-Chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of6-(N-(3-chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(210 mg, 0.37 mmol) in THF (7 mL) was added DIEA (0.084 mL, 0.48 mmol)and chloromethyl methyl ether (0.16 mL, 2.12 mmol). The reaction mixturewas heated at 50° overnight. Another portion of DIEA (0.32 mL, 1.85mmol) was added and heating was continued for another 5 h. The reactionmixture was cooled to rt, diluted with water and extracted with EtOAc(2×). The combined organic layers were washed with brine (1×), driedover sodium sulfate and concentrated under reduced pressure.Purification by flash chromatography (silica gel, gradient of 0 to 60%EtOAc in hexanes) afforded the title compound (175 mg, 77%) as acolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.45 (q, 1H), 8.10 (s,1H), 7.93-8.00 (m, 2H), 7.36-7.53 (m, 5H), 7.19 (s, 1H), 5.88 (ddd, 1H),5.38 (d, 1H), 5.18-5.30 (m, 2H), 4.66 (d, 1H), 4.53 (d, 1H), 3.38-3.46(m, 3H), 3.23 (s, 3H), 2.83 (d, 3H), 2.08-2.17 (m, 1H), 0.92-1.06 (m,1H), 0.75-0.91 (m, 2H), 0.39-0.51 (m, 1H). LCMS (m/z, ES⁺)=613 (M+H+).

Step 5:6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of6-(N-(3-chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(125 mg, 0.20 mmol) in THF (10 mL) was treated with Rh(CO)Cl(PPh₃)₂(14mg, 0.02 mmol), purged with nitrogen and treated with a solution ofpinacolborane (1 M in THF, 1.22 mL). After stirring overnight at rt, thereaction mixture was concentrated. The residue was dissolved in THF (10mL) and treated with (Ir(COD)Cl)₂ (13.7 mg, 0.02 mmol) and DPPE (16.3mg, 0.041 mmol). After stirring for 5 min, a solution of pinacolborane(1 M in THF, 1.22 mL) was added. The reaction mixture was stirred for 2h and concentrated under reduced pressure. Separately, the aboveprocedure was repeated, using the same sequence of steps, on6-(N-(3-chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(49 mg, 0.08 mmol), using proportional quantities of identical reagents.Both of these residues were subjected to purification by flashchromatography (silica gel, gradient of 0 to 100% EtOAc in hexanes) toafford a pale yellow oil which was carried forward withoutcharacterization. The oil was dissolved in THF (5 mL) and 1N HCl (5 mL)and heated at 70° for 16 h, at which time methanol (1 mL) was added andthe heating continued for 1 h. The reaction mixture was cooled to rt,diluted with water and extracted with EtOAc (2×). The combined organiclayers were washed with brine (1×), dried over sodium sulfate andconcentrated under reduced pressure. Purification by flashchromatography (silica gel, gradient of 0 to 100% ethyl acetate indichloromethane, then 0 to 3.5% methanol in dichloromethane) affordedthe title compound (32 mg, 19% over 2 steps) as an off-white foam. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.79 (s, 1H), 8.45 (q, 1H), 8.12 (s, 1H),7.91-8.01 (m, 2H), 7.34-7.54 (m, 5H), 7.18 (s, 1H), 5.32 (t, 1H),3.38-3.44 (m, 3H), 2.83 (d, 3H), 2.36-2.46 (m, 1H), 2.09-2.21 (m, 1H),1.49-1.63 (m, 1H), 0.76-1.09 (m, 5H), 0.35-0.55 (m, 1H). LCMS (m/z,ES⁺)=597 (M+H+).

Example 286-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 1

Step 1:6-(N-(3-Chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomers 1 and 2

A solution of6-(N-(3-chloro-4-formylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(1.17 g, 2.16 mmol) in THF (20 mL) was cooled to 0° and treated withvinylmagnesium bromide (1 M in THF, 4.76 mL). The reaction mixture wasallowed to warm to rt as the bath melted. An additional portion ofvinylmagnesium bromide (0.43 mL,) was added after a few h. Stirring wascontinued and the reaction mixture was poured into saturated ammoniumchloride and extracted with EtOAc (2×). The combined organic layers weredried over sodium sulfate and concentrated under reduced pressure.Purification by flash chromatography (silica gel, gradient of 0 to 60%EtOAc in hexanes) afforded the title compound (0.87 g, 71%) as a whitefoam. Enantiomers were separated by supercritical fluid chromatography(Chiral Tech ADH, 30% methanol, 140 bar, 40° C., 90 mL/min). Bothenantiomers were white foams. The earlier eluting enantiomer 1 weighed380 mg and the later eluting enantiomer 2 weighed 370 mg. Enantiomer #1¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (q, 1H), 8.11 (s, 1H), 7.93-8.01(m, 2H), 7.35-7.55 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.70 (d, 1H),5.35 (t, 1H), 5.22 (dt, 1H), 5.08 (dt, 1H), 3.40 (s, 3H), 2.83 (d, 3H),2.10-2.20 (m, 1H), 0.77-1.06 (m, 3H), 0.40-0.53 (m, 1H). LCMS (m/z,ES⁺)=569 (M+H+). Enantiomer #2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (q,1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.36-7.56 (m, 5H), 7.18 (s, 1H),5.90 (ddd, 1H), 5.70 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.08 (dt,1H), 3.40 (s, 3H), 2.83 (d, 3H), 2.09-2.20 (m, 1H), 0.76-1.06 (m, 3H),0.40-0.54 (m, 1H). LCMS (m/z, ES⁺)=569 (M+H+).

Step 2:6-(N-(3-Chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 1

To a solution of6-(N-(3-chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 1 (350 mg, 0.62 mmol) in THF (10 mL) was added DIEA (0.32 mL,1.85 mmol) and chloromethyl methyl ether (0.12 mL, 1.54 mmol). Thereaction mixture was heated at 50° overnight. Additional portions ofDIEA (0.32 mL, 1.85 mmol) and chloromethyl methyl ether (0.12 mL, 1.54mmol) were added and heating was continued for another 24 h. Thereaction mixture was cooled to rt, diluted with water and extracted withEtOAc (2×). The combined organic layers were washed with brine (1×),dried over sodium sulfate and concentrated under reduced pressure.Purification by flash chromatography (silica gel, gradient of 0 to 50%EtOAc in hexanes) afforded the title compound (350 mg, 93%) as acolorless semisolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (q, 1H), 8.10(s, 1H), 7.91-7.99 (m, 2H), 7.35-7.52 (m, 5H), 7.18 (s, 1H), 5.87 (ddd,1H), 5.36 (d, 1H), 5.17-5.29 (m, 2H), 4.65 (d, 1H), 4.52 (d, 1H), 3.42(s, 3H), 3.22 (s, 3H), 2.82 (d, 3H), 2.05-2.17 (m, 1H), 0.92-1.04 (m,1H), 0.73-0.89 (m, 2H), 0.37-0.50 (m, 1H). LCMS (m/z, ES⁺)=613 (M+H+).

Step 5:6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 1

A solution of6-(N-(3-chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 1 (52 mg, 0.085 mmol) in THF (5 mL) was treated with(Ir(COD)Cl)₂ (5.7 mg, 8.5 μmol) and DPPE (6.8 mg, 0.017 mmol). Afterstirring for 25 min, a solution of pinacolborane (1 M in THF, 0.25 mL)was added. The reaction mixture was stirred for 0.5 h and concentratedunder reduced pressure. Separately, the above procedure was repeated,using proportional quantities of reagents, on6-(N-(3-chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 1 (296 mg, 0.48 mmol). The two residues were subjected topurification by flash chromatography (silica gel, gradient of 0 to 100%EtOAc in hexanes) to afford a colorless oil which was carried forwardwithout characterization. The oil was dissolved in THF (10 mL), 1N HCl(10 mL) and MeOH (1 mL) and heated at 70° for 16 h. The reaction mixturewas cooled to rt, diluted with water and extracted with EtOAc (2×). Thecombined organic layers were washed with brine (1×), dried over sodiumsulfate and concentrated under reduced pressure. Purification by flashchromatography (silica gel, gradient of 0 to 100% ethyl acetate indichloromethane, then 0 to 3.5% methanol in dichloromethane) followed bylyophilization afforded the title compound (85 mg, 25% over 2 steps) asa fluffy white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (s, 1H),8.40-8.49 (m, 1H), 8.12 (s, 1H), 7.92-8.03 (m, 2H), 7.34-7.56 (m, 5H),7.19 (s, 1H), 5.29-5.37 (m, 1H), 3.38-3.46 (m, 3H), 2.84 (d, 3H),2.37-2.47 (m, 1H), 2.10-2.22 (m, 1H), 1.50-1.73 (m, 1H), 0.75-1.08 (m,5H), 0.37-0.56 (m, 1H). LCMS (m/z, ES⁺)=597 (M+H+).

Example 296-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 2

Step 1:6-(N-(3-Chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 2

To a solution of6-(N-(3-chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 2 (340 mg, 0.58 mmol) in THF (7 mL) was added DIEA (0.42 mL,2.39 mmol) and chloromethyl methyl ether (0.14 mL, 1.79 mmol). Thereaction mixture was heated at 50° overnight. Additional portions ofDIEA (0.42 mL, 2.39 mmol) and chloromethyl methyl ether (0.14 mL, 1.79mmol) were added and heating was continued for another 24 h. Thereaction mixture was cooled to rt, diluted with water and extracted withEtOAc (2×). The combined organic layers were washed with brine (1×),dried over sodium sulfate and concentrated under reduced pressure.Purification by flash chromatography (silica gel, gradient of 0 to 50%EtOAc in hexanes) afforded the title compound (342 mg, 93%) as acolorless semisolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.45-8.51 (m, 1H),8.12 (s, 1H), 7.94-8.02 (m, 2H), 7.37-7.54 (m, 5H), 7.20 (s, 1H), 5.89(ddd, 1H), 5.38 (d, 1H), 5.18-5.32 (m, 2H), 4.67 (d, 1H), 4.54 (d, 1H),3.44 (s, 3H), 3.24 (s, 3H), 2.84 (d, 3H), 2.08-2.19 (m, 1H), 0.77-1.06(m, 3H), 0.41-0.51 (m, 1H). LCMS (m/z, ES⁺)=613 (M+H+).

Step 2:6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 2

A solution of6-(N-(3-chloro-4-(1-(methoxymethoxy)allyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 2 (340 mg, 0.56 mmol) in THF (15 mL) was treated with(Ir(COD)Cl)₂ (37 mg, 0.055 mmol) and DPPE (44 mg, 0.11 mmol). Afterstirring for 30 min, a solution of pinacolborane (1 M in THF, 1.66 mL)was added. The reaction mixture was stirred for 0.5 h and concentratedunder reduced pressure. The residue was subjected to purification byflash chromatography (silica gel, gradient of 0 to 100% EtOAc inhexanes) to afford a colorless oil which was carried forward withoutcharacterization. The oil was dissolved in THF (10 mL), 1N HCl (10 mL)and MeOH (1 mL) and heated at 70° for 16 h. The reaction mixture wascooled to rt, diluted with water and extracted with EtOAc (2×). Thecombined organic layers were washed with brine (1×), dried over sodiumsulfate and concentrated under reduced pressure. Purification by flashchromatography (silica gel, gradient of 0 to 100% ethyl acetate indichloromethane, then 0 to 3.5% methanol in dichloromethane) followed bylyophilization afforded the title compound (124 mg, 38% over 2 steps) asa fluffy white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.79 (s, 1H),8.42-8.49 (m, 1H), 8.12 (s, 1H), 7.93-8.02 (m, 2H), 7.35-7.55 (m, 5H),7.19 (s, 1H), 5.33 (t, 1H), 3.39-3.45 (m, 3H), 2.84 (d, 3H), 2.37-2.47(m, 1H), 2.12-2.22 (m, 1H), 1.49-1.64 (m, 1H), 0.77-1.07 (m, 5H),0.41-0.52 (m, 1H). LCMS (m/z, ES⁺)=597 (M+H+).

Example 305-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-6-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Step 1: Dimethyl2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)malonate

To a stirred suspension of Cs₂CO₃ (17.5 g, 53.8 mmol) in DMF (20 ml)under a nitrogen atmosphere was added dimethyl malonate (2.57 mL, 22.4mmol) at room temperature. This was followed by the addition of asonicated solution of6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(10.0 g, 17.9 mmol) in DMF (50 mL) at room temperature by dropwiseaddition. The reaction mixture was stirred at room temperature for 24 h.The reaction mixture was diluted with water and extracted with EtOAc(3×40 mL). The organic layer was washed with water (3×50 mL), dried oversodium sulfate and evaporated to dryness. The crude product trituratedwith ether and the solid collected by filtration to afford the titlecompound in 68% yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (d, J=4.7Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 8.04 (s, 1H), 7.90-8.00 (m, 2H),7.36-7.51 (m, 3H), 7.26-7.31 (m, 1H), 7.14-7.20 (m, 1H), 5.45-5.56 (m,1H), 3.52-3.64 (m, 9H), 2.84 (d, J=4.5 Hz, 3H), 1.88-2.03 (m, 1H),0.82-1.00 (m, 2H), 0.69 (d, J=3.1 Hz, 1H), 0.29-0.50 (m, 1H). LCMS (m/z,ES⁺)=654 (M+H+).

Step 2:2-(5-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)aceticacid

To a stirred solution of dimethyl2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)malonate(10.0 g, 15.3 mmol) in 1:1:1 THF/MeOH/water, was added 3N aqueous NaOH(20 mL). The resulting mixture was heated at 55° C. for 15 h. Thereaction mixture was cooled to room temperature and treated with 5Naqueous HCl to pH 5. The aqueous layer was extracted with ethyl acetate(3×30 mL). The organic layer was washed with water, dried over sodiumsulfate and evaporated to dryness. The residue was triturated withmethanol and ether and the solid collected by filtration to give thetitle compound in 75% yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.52 (br.s., 1H) 8.49 (q, J=4.23 Hz, 1H) 8.09-8.15 (m, 1 H) 8.02 (s, 1H) 7.96 (d,J=3.32 Hz, 4H) 7.31-7.44 (m, 4H) 7.25 (s, 1H) 3.98 (s, 2H) 3.56 (s, 3H)2.84 (d, J=4.69 Hz, 3H) 1.94-2.03 (m, 1H) 0.85 (d, J=3.13 Hz, 3H) 0.48(br. s., 1H). LCMS (m/z, ES⁺)=583 (M+H+).

Step 3: Methyl2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)acetate

To a stirred solution of2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)aceticacid (2.00 g, 3.44 mmol) in 10 mL of 1:1 DMF/MeOH was added 2 MTMS-diazomethane in hexane (0.786 g, 6.88 mmol) at 0° C. and reactionmixture stirred for 2 h. The reaction was diluted with water andextracted into EtOAc. The ethyl acetate solution was washed with water,dried over sodium sulfate and evaporated to dryness to give the titlecompound in 70% yield. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.04 (d,J=9.19 Hz, 1H) 7.88 (br. s., 0H) 7.80 (t, J=6.06 Hz, 2H) 7.46 (s, 1H)7.44 (br. s., 1H) 7.28 (dd, J=9.18, 1.95 Hz, 1H) 7.08-7.18 (m, 3H) 6.13(br. s., 1H) 3.88 (s, 2H) 3.62 (s, 3H) 3.29 (s, 3H) 2.93 (d, J=2.93 Hz,3H) 2.88 (s, 2H) 2.79 (d, J=1.76 Hz, 1H) 1.82-1.93 (m, 1H) 0.67-0.98 (m,3H) 0.49 (br. s., 1H). LCMS (m/z, ES⁺)=596 (M+H+).

Step 4: Methyl2-(2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)acetate

A solution of methyl2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methyl-carbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)acetate(1.00 g, 1.68 mmol) in THF (10 mL) was subjected to atmospherichydrogenation in the presence of 20% palladium on charcoal. After 10hours the reaction vessel was purged with nitrogen, catalyst removed byfiltration through Celite, and the filtrate concentrated to dryness atreduced pressure. The crude material was subjected to flashchromatography (silica gel, hexane/EtOAc) to give the title compound in65% yield. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84-7.92 (m, 2H) 7.68(s, 1H) 7.39 (s, 1H) 7.23-7.30 (m, 3H) 7.18 (t, J=8.60 Hz, 2H) 6.66 (d,J=8.40 Hz, 1H) 5.84 (d, J=4.49 Hz, 1H) 4.11-4.19 (m, 2H) 3.68 (s, 3H)3.52 (s, 2H) 3.14-3.20 (m, 3H) 2.94-3.02 (m, 3H) 2.21-2.30 (m, 1H) 0.96(br. s., 2H). LCMS (m/z, ES⁺)=566 (M+H+).

Step 5:6-(N-(4-Amino-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of methyl2-(2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)acetate(500 mg, 0.884 mmol) in THF (6 mL) at 0° C. was added 3.5M lithiumaluminum hydride/THF (0.20 mL, 0.71 mmol). After stirring for 45 minutesat 0° C. aqueous work-up followed by flash chromatography (silica gel,hexane/EtOAc) afforded the title compound in 65% yield. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.89 (dd, J=7.82, 5.47 Hz, 1H) 7.70 (s, 0H) 7.40 (s,1H) 7.15-7.25 (m, 2H) 6.61-6.73 (m, 1H) 5.78 (br. s., 0H) 3.89 (t,J=5.96 Hz, 1H) 3.18 (s, 2H) 3.10-3.24 (m, 3H) 3.00 (d, J=4.89 Hz, 1H)2.76 (t, J=5.86 Hz, 1H) 2.29 (br. s., 0H) 0.99 (br. s., 2H). LCMS (m/z,ES⁺)=538 (M+H+).

Step 6:6-(N-(4-Bromo-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a solution of6-(N-(4-amino-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(250 mg, 0.465 mmol) in MeCN (1 mL) maintained at 0° C. was added sodiumnitrite (80 mg, 1.16 mmol) dissolved in water (0.50 mL). followed by 48%aqueous HBr (0.25 mL). The resulting mixture was treated with copper(I)bromide (133 mg, 0.930 mmol) in 48% aqueous HBr (0.30 mL). Afterstirring at 60° C. for 1 hour the reaction mixture was cooled to RT,diluted with water and extracted with EtOAc. The organic solution waswashed with water, dried over sodium sulfate, and concentrated todryness at reduced pressure. The crude product was purified by flashchromatography (silica gel, hexane/EtOAc) to afford the title compoundin 65% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.36-8.51 (m, 1H) 8.05 (s,1H) 7.92 (dd, J=8.89, 5.37 Hz, 2H) 7.49-7.62 (m, 1H) 7.31-7.49 (m, 3H)7.09-7.26 (m, 2H) 4.69 (t, J=5.28 Hz, 1H) 3.46-3.60 (m, 2H) 3.30-3.40(m, 3H) 2.72-2.87 (m, 5H) 2.04-2.22 (m, 1H) 0.70-1.06 (m, 3H) 0.41 (br.s., 1H).). LCMS (m/z, ES⁺)=601,603 (M+H+).

Step 7:5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-6-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

To a deoxygenated solution of6-(N-(4-bromo-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(100 mg, 0.166 mmol) in 1,4-dioxane (4 mL) and water (1.0 mL) was addedK₂CO₃ (92 mg, 0.665 mmol) followed by4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (84 mg, 0.33mmol) and PdCl₂(dppf) (12.16 mg, 0.017 mmol) under nitrogen purging.Then the reaction mixture was heated to 70° C. for 2 h. The mixture wascooled to RT and filtered to remove solids. The filtrate was dilutedwith water and extracted with EtOAc. The EtOAc solution was washed withwater (1×), dried over sodium sulfate, and concentrated to dryness atreduced pressure. The crude product was purified by RP-HPLC (C18,MeCN/water/0.1% formic acid) to afford the title compound in 65% yield.¹H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J=8.60, 5.28 Hz, 2H) 7.67-7.71(m, 1H) 7.57-7.62 (m, 1H) 7.45-7.49 (m, 1H) 7.13-7.25 (m, 4H) 5.79 (d,J=3.91 Hz, 1H) 4.31 (s, 1H) 4.19 (t, J=5.96 Hz, 2H) 3.29 (s, 3H) 3.01(d, J=4.89 Hz, 3H) 2.89 (t, J=5.86 Hz, 2H) 2.02-2.13 (m, 1H) 1.02 (br.s., 1H) 0.83 (br. s., 2H) 0.61 (br. s., 1H). LCMS (m/z, ES⁺)=549 (M+H+).

Example 316-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Step 1: methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate

A mixture of 55.0 g (123 mmol) of5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide,36.7 g (184 mmol) of methyl 5-fluoro-2-nitrobenzoate, and 39.1 g (369mmol) of sodium carbonate in 400 mL of DMF was heated to 70° C. withvigorous stirring. After 72 hours LCMS indicated nearly completereaction. The mixture was cooled to RT, diluted with 300 mL of EtOAc,and filtered through a bed of celite to remove solids. The filter cakewas washed with EtOAc until the filtrate ran colorless which gave atotal filtrate volume of 1.2 L. The filtrate was transferred to aseparatory funnel, partitioned with 1.4 L of 5% aqueous NaCl, and thephases separated. The aqueous solution was extracted with two additional300 mL portions of EtOAc. The combined EtOAc solutions were washed with95% aqueous NaCl (2×), saturated aqueous NaCl (1×), dried over sodiumsulfate and concentrated to approximately 200 mL by rotary evaporation.At this point a solid began to crystallize. The suspension was dilutedwith 200 mL of DCM and the suspension stirred overnight. The suspensionwas then cooled in an ice water bath for 2 hours and the solid collectedby vacuum filtration. The filter cake was washed twice with cold 1:1EtOAc/DCM, suction air dried for 30 minutes and then dried in vacuoovernight to afford 59.6 g (83%) of methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoateas a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.52 (q, J=4.42Hz, 1H) 8.13 (d, J=9.07 Hz, 1H) 8.08 (s, 1H) 7.93-8.01 (m, 2H) 7.57 (d,J=2.63 Hz, 1H) 7.53 (dd, J=9.07, 2.73 Hz, 1H) 7.38-7.46 (m, 2H) 7.29 (s,1H) 3.83 (s, 3H) 3.60 (s, 3H) 2.85 (d, J=4.59 Hz, 3H) 1.87-2.04 (m, 1H)0.87 (m, 2H) 0.73 (m, 1H) 0.46 (m, 1H). LCMS(ESI): 582 (M+H+).

Step 2: methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

A stirred suspension of 59.5 g (102 mmol) of methyl5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoateand 6.0 g of 10% Pd(C) in 1.2 L of 2:1 THF/EtOH was saturated withhydrogen by bubbling hydrogen gas through for 10 minutes and thensubjected to balloon hydrogenation at RT. After 6 hours LCMS indicatedcomplete reaction. After 24 hours the mixture was purged with nitrogen,catalyst removed by filtration through celite, and the filtrateconcentrated to dryness at reduced pressure to give a light yellowsolid. This material was recrystallized from hot EtOAc to afford 42.2 gof methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoateas a white solid. The filtrate was concentrated to dryness at reducedpressure to give an additional 13.0 g of methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoateas a light yellow foam determined to be 95% pure by LCMS. The twobatches were combined for a total yield of 55.2 g (98%) of methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (q, J=4.42 Hz, 1H) 8.16 (s, 1H)7.91-8.00 (m, 3H) 7.61 (dd, J=8.98, 2.73 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H)7.15 (s, 1H) 6.76-6.86 (m, 3H) 3.79 (s, 3H) 3.28 (s, 3H) 2.83 (d, J=4.68Hz, 3H) 2.25-2.38 (m, 1H) 0.82-1.10 (m, 3H) 0.42 (m, 1H). LCMS(ESI): 552(M+H+).

Step 3: methyl2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

A suspension of 55.0 g (100 mmol) of methyl2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoatein 320 mL of DMF was heated to 60° C. The resulting yellow solution wastreated with 14.0 g (105 mmol) of NCS in one portion. The solutionquickly darkened. After 5 minutes LCMS indicated complete conversion tothe desired chloro compound. The solution was cooled to RT and dilutedwith 1 L of EtOAc. The resulting solution was washed with 5% aqueousNaCl (1×1 L), 5% aqueous sodium bisulfite (2×200 mL), saturated aqueoussodium bicarbonate (3×200 mL), and saturated aqueous brine (1×200 mL).The solution was dried over sodium sulfate and concentrated to drynessat reduced pressure to give 58.0 g (99%) of methyl2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoateas a brown solid. This material was taken forward to the next stepwithout purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (q, J=4.42Hz, 1H) 8.25 (s, 1H) 7.94-8.04 (m, 3H) 7.90 (d, J=2.63 Hz, 1H) 7.34-7.46(m, 2H) 7.18 (s, 1H) 6.93 (br. s., 2H) 3.83 (s, 3H) 3.33 (s, 3H) 2.84(d, J=4.59 Hz, 3H) 2.26-2.36 (m, 1H) 0.84-1.11 (m, 3H) 0.40 (br. s.,1H). LCMS(ESI): 586 (M+H+).

Step 4: methyl2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

To a 1 L 3-necked flask equipped with a magnetic stirrer was added 58.0g (99.0 mmol) of methyl2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoatefollowed by 500 mL of MeCN and then 500 mL of 48% aqueous HBr. The darkbrown solution was cooled to 0° C. in an ice water/brine bath andtreated with a solution of 8.20 g (119 mmol) of sodium nitrite in 50 mLof water over a 5 minute period. After 30 minutes LCMS indicatedcomplete consumption of the starting material. The solution was treatedwith 18.5 g (129 mmol) of CuBr over 2 minutes and then warmed to 50° C.After 30 minutes at 50° C. LCMS indicated complete reaction. Thesolution was cooled to RT and partitioned between 1 L of EtOAc and 1.5 Lof water. The phases were separated and the aqueous solution extractedwith EtOAc (2×200 mL). The combined EtOAc solutions were washed with 5%aqueous NaCl (1×1 L), 5% aqueous sodium bisulfite (2×300 mL), saturatedaqueous sodium bicarbonate (2×300 mL), saturated aqueous brine (1×300mL), and dried over sodium sulfate. The drying agent was removed byfiltration through a pad of silica gel and the filtrate concentrated todryness at reduced pressure to give 64.3 g of crude methyl2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoateas a reddish-brown foam. The crude product was carried forward withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.50 (q, J=4.29Hz, 1H) 8.16 (s, 1H) 7.92-8.03 (m, 2H) 7.79 (d, J=2.73 Hz, 1H) 7.65 (d,J=2.73 Hz, 1H) 7.41 (t, J=8.93 Hz, 2H) 7.24 (s, 1H) 3.81-3.89 (m, 3H)3.45-3.53 (m, 3H) 2.85 (d, J=4.59 Hz, 3H) 2.04-2.16 (m, 1H) 0.71-1.07(m, 3H) 0.40 (br. s., 1H). LCMS(ESI): 649 (M+H+).

Step 5:6-(N-(4-bromo-3-chloro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 54.3 g (84.0 mmol) of crude methyl2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoatein 351 mL of anhydrous THF and 39 mL of anhydrous MeOH was cooled in anice water/brine bath to −5° C. (internal temperature). To the stirredsolution was added 125 mL (251 mmol) of 2M LiBH₄/THF via addition funnelat a rate so as to maintain the temperature below 5° C. The additionrequired 35 minutes. The brine bath was then replaced by an ice waterbath and stirring of the solution continued. After another 1.5 hoursLCMS indicated complete reaction. The solution was quenched by additionof 200 mL of saturated aqueous sodium bicarbonate followed by 400 mL ofwater and 600 mL of EtOAc. The mixture was stirred vigorously for 30minutes and then transferred to a separatory funnel. After the phasesseparated, solid remained in the aqueous phase so an additional 200 mLof water was added and the mixture shaken, and the phases againseparated. The aqueous solution was extracted with EtOAc (2×200 mL). Thecombined EtOAc solutions were washed with 5% aqueous NaCl (1×),saturated brine (1×), dried over sodium sulfate and concentrated todryness at reduced pressure to afford 54.5 g of6-(N-(4-bromo-3-chloro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas an orange-brown foam. The crude material was carried forward to thenext step without purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.45-8.54 (m, 1H) 8.12 (s, 1H) 7.98 (dd, J=8.93, 5.41 Hz, 2H) 7.59 (d,J=2.73 Hz, 1H) 7.54 (d, J=2.63 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.22 (s,1H) 5.64 (t, J=5.56 Hz, 1H) 4.48 (d, J=5.56 Hz, 2H) 3.45 (s, 3H) 2.84(d, J=4.59 Hz, 3H) 2.06-2.17 (m, 1H) 0.75-1.06 (m, 3H) 0.47 (br. s.,1H). LCMS(ESI): 623 (M+H+).

Step 6:6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of 50.0 g (80.0 mmol) of crude6-(N-(4-bromo-3-chloro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamidein 500 mL of THF was treated with 42.1 mL (241 mmol) of DIEA followed by15.3 mL (201 mmol) of MOM-Cl and the resulting solution was heated to50° C. with stirring. After 18 hours LCMS indicated complete reaction.The solution was cooled to RT and diluted with 600 mL of EtOAc followedby 600 mL of water. After stirring vigorously for 10 minutes the mixturewas transferred to a separatory funnel and the phases separated. Theaqueous phase was extracted with one additional 200 mL portion of EtOAc.The combined EtOAc solutions were washed with an aqueous solution of 5%citric acid and 5% NaCl (3×300 mL), saturated aqueous sodium bicarbonate(2×300 mL), saturated brine (1×300 mL), and dried over sodium sulfate.The drying agent was removed by filtration and the filtrate concentratedto dryness at reduced pressure to give an orange-brown foam. Thismaterial was dissolved in 250 mL of EtOAc and the solution heated toreflux with stirring. To the solution was added 375 mL of hexane over a5 minute period maintaining reflux temperature. The solution was thenallowed to cool to RT with stirring during which time a light tan solidcrystallized. After 2 hours the solution was cooled in an ice water bathand stirred for an additional 2 hours. The solid was collected byfiltration in a medium fritted funnel. The filter cake was washed with250 mL of cold 3:2 hexane/EtOAc, dried by suction filtration for 30minutes, and then dried in vacuo to give 36.4 g of6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a light tan solid. ¹H NMR (400 MHz, DMSO-d₆) ppm 8.49 (q, J=4.30 Hz,1H) 8.14 (s, 1H) 7.93-8.00 (m, 2H) 7.62 (d, J=2.74 Hz, 1H) 7.52 (d,J=2.74 Hz, 1H) 7.40 (t, J=8.94 Hz, 2H) 7.21 (s, 1H) 4.68 (s, 2H) 4.57(s, 2H) 3.44 (s, 3H) 3.24 (s, 3H) 2.83 (d, J=4.59 Hz, 3H) 2.06-2.19 (m,1H) 0.74-1.05 (m, 3H) 0.44 (br. s., 1H).

Step 7:6-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A mixture of 46.4 g (69.7 mmol) of6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,44.2 g of bis(pinacolato)diboron (174 mmol), 27.4 g (279 mmol) ofpotassium acetate, and 2.10 g (3.48 mmol) of Pd(dppb)Cl₂ in 350 mL of1,4-dioxane was sparged with nitrogen for 15 minutes and then heated to108° C. under nitrogen. After 22 hours LCMS showed complete conversionof starting material to an 84:16 mixture of desired product/protioby-product (replacement of bromine by hydrogen). The mixture was cooledto RT, combined with the crude reaction mixture from a 1 g scale pilotreaction, and diluted with 500 mL of EtOAc. The mixture was filteredthrough a pad of silica gel to remove solids and the filtrate wasconcentrated at reduced pressure to give 93.1 g of6-(N-(3-chloro-5-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a light tan solid. LCMS(ESI): 713 (M+H+). This material was dissolvedin 524 mL of 5:1 THF/MeOH and the solution treated with 440 mL of 1Naqueous HCl. A tan solid rapidly precipitated. The mixture was heated to70° C. The solid slowly dissolved affording a yellow solution. After 18hours LCMS indicated complete reaction. The solution was cooled toapproximately 40° C. and poured into a rapidly stirred mixture of 1 L ofwater and 1 L of MTBE. To the mixture was added 440 mL of 1N aqueousNaOH. The pH was then adjusted to around 12-13 by addition of 3N aqueousNaOH. The mixture was transferred to a separatory funnel and the phasesseparated. Analysis of the two phases by TLC and LCMS indicated nearlycomplete separation of the desired product from the protio by-product.The aqueous phase was washed with MTBE (3×250 mL) and then treated withconcentrated HCl to a pH of approximately 2. The resulting cloudysolution was extracted with EtOAc (4×500 mL). The combined EtOAcextracts were washed with 5% aqueous brine (1×), saturated aqueous brine(1×), and dried over sodium sulfate. The drying agent was removed byfiltration through a pad of celite to give a light yellow filtrate. Thefiltrate was concentrated to dryness at reduced pressure to give 39.0 gof a tan foam. This material was dissolved in 400 mL of MeCN. Theresulting solution was stirred with slow addition of 800 mL of 0.1Naqueous HCl via addition funnel over a 40 minute period. Early in theaddition the solution was seeded with a small amount of previouslyprepared, crystalline6-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamidewhich induced vigorous crystallization. The suspension was stirredovernight at RT. The solid was collected by vacuum filtration rinsingwith 2:1 MeCN water. The material was suction air dried for 1 hour andthen dried to constant weight in vacuo to afford 28.8 g (71%) of6-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas an off-white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.18 (s, 1H)8.50 (q, J=4.42 Hz, 1H) 8.09 (s, 1H) 7.93-8.02 (m, 2H) 7.37-7.46 (m, 3H)7.28 (d, J=1.56 Hz, 1H) 7.22 (s, 1H) 4.97 (s, 2H) 3.48 (s, 3H) 2.85 (d,J=4.59 Hz, 3H) 2.02-2.14 (m, 1H) 0.92-1.04 (m, 1H) 0.82 (br. s., 2H)0.49 (br. s., 1H). LCMS(ESI): 569 (M+H+).

Example 32 Pharmaceutical Composition

Quantity Component (mg/tablet) Compound of Example 15, Spray 14.00 DriedDispersion Microcrystalline Cellulose (~100 μm) 5.50 MicrocrystallineCellulose (~20 μm) 4.31 Croscarmellose Sodium 0.752 Colloidal SiliconeDioxide 0.25 Magnesium Stearate 0.188 Total Tablet Weight (mg/tablet)25.0

A solution of4-((N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl)-2-fluorophenylboronicacid and hypromellose acetate succinate can be prepared in acetone forspray drying. The solution can be spray dried and then the resultingpowder can be dried. This can provide an amorphous spray drieddispersion. The spray dried dispersion can then be blended withmicrocrystalline cellulose (˜20 μm particle size). CroscarmelloseSodium, Colloidal Silicon Dioxide and microcrystalline cellulose (˜100μm particle size) can then added and blended. Magnesium stearate canthen be added and blended further. The blend can then be compressed intotablets.

Example 33 Pharmaceutical Composition

Quantity Component (mg/tablet) Compound of Example 15, Spray 420 DriedDispersion Microcrystalline Cellulose (~100 μm) 165 MicrocrystallineCellulose (~20 μm) 129.3 Croscarmellose Sodium 22.56 Colloidal SiliconeDioxide 7.5 Magnesium Stearate 5.64 Total Tablet Weight (mg/tablet) 750

A tablet may be prepared according to the procedure of Example 32 usingthe quantities from the table above.

Example 34 Pharmaceutical Composition

Quantity Component (mg/tablet) Compound of Example 15, Spray 420 DriedDispersion Ribavirin 400 Microcrystalline Cellulose (~100 μm) 165Microcrystalline Cellulose (~20 μm) 129.3 Croscarmellose Sodium 22.56Colloidal Silicone Dioxide 7.5 Magnesium Stearate 5.64 Total TabletWeight (mg/tablet) 1150

A tablet, further comprising ribavirin, may be prepared according to theprocedure of Example 32 using the quantities from the table above.

Example 35 Pharmaceutical Composition

Quantity Component (mg/tablet) Compound of Example 15, Spray 420 DriedDispersion Ritonavir 100 Microcrystalline Cellulose (~100 μm) 165Microcrystalline Cellulose (~20 μm) 129.3 Croscarmellose Sodium 22.56Colloidal Silicone Dioxide 7.5 Magnesium Stearate 5.64 Total TabletWeight (mg/tablet) 850

A tablet, further comprising ritonavir, may be prepared according to theprocedure of Example 32 using the quantities from the table above.

1. A method of treatment of Hepatitis C Virus (HCV) in a human in needthereof comprising administering a compound of Formula (II):

wherein: R is independently selected from the group consisting ofhalogen, C₁₋₆alkyl, alkoxy, —CN, —CF₃, —O—C₆₋₁₀aryl optionallysubstituted by halogen, and —O-heteroaryl optionally substituted byhalogen; R¹ is —C(O)OH, —C(O)NHR⁵ or heterocyclyl; R² is C₁₋₆alkyl,C₃₋₆cycloalkyl, —C(H)F₂, —CF₃, or —OR⁶; R³ is —S(O)₂R⁷ or —C(O)R⁷; R⁴ is(a) heteroaryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; (b)C₆₋₁₀aryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; Het is a 5 or 6-memberedmonocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclicring system any ring of which is either saturated, partially saturatedor unsaturated, which may be optionally benzofused if monocyclic orwhich may be optionally spiro-fused, and wherein each Het consists ofone or more carbon atoms and one boron atom and one or more oxygenatoms; one boron atom, one oxygen atom, and one nitrogen atom; or oneboron atom and one or more nitrogen atoms; R⁵ is hydrogen, C₁₋₆alkyl,hydroxy, or —OR⁶; R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁷ is C₁₋₆alkyl,hydroxyalkyl, or aminoalkyl; R⁸, R⁹, and R¹² are each independentlyhydroxy, alkoxy, or aminoalkyl; or R⁸ and R⁹ or R⁸, R⁹, and R¹² togetherwith the boron atom to which they are attached form a 5 to 14-memberedring, said ring comprising carbon atoms and optionally one or moreheteroatoms which can be N or O; said ring may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH,C(O)OXOR¹³, C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹),) and C₃₋₆cycloalkyl each ofwhich may be optionally substituted with one or more substituentsindependently selected from the group consisting of hydroxy, amino,halogen, C(O)OH, C(O)N(R¹⁰)(R¹¹) and N(R¹⁰)(R¹¹); R¹⁰ and R¹¹ are eachindependently hydrogen or C₁₋₆alkyl; R¹³ is alkoxy; X is alkylene or—O-alkylene, wherein alkylene is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰ and C₃₋₆cycloalkyl; m is 1, 2, or 3;or a pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue.
 2. A method of treatment of Hepatitis C Virus (HCV)in a human in need thereof comprising administering a compound ofFormula (IIB):

wherein: R is F or Cl; R¹ is —C(O)NHR⁵; R² is C₃₋₆cycloalkyl; R³ is—S(O)₂R⁷; R⁴ is (a) heteroaryl substituted with B(R⁸)(R⁹) or XB(R⁸)(R⁹),and optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂,—CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH,—C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl; (b) C₆₋₁₀aryl substituted withB(R⁸)(R⁹), or XB(R⁸)(R⁹), and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; Het is a 5 or 6-memberedmonocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclicring system any ring of which is either saturated, partially saturatedor unsaturated, which may be optionally benzofused if monocyclic orwhich may be optionally spiro-fused, and wherein each Het consists ofone or more carbon atoms and one boron atom and one or more oxygenatoms; one boron atom, one oxygen atom, and one nitrogen atom; or oneboron atom and one or more nitrogen atoms; R⁵ is C₁₋₆alkyl; R⁶ isC₁₋₆alkyl or C₃₋₆cycloalkyl; R⁷ is C₁₋₆alkyl, hydroxyalkyl, oraminoalkyl; R⁸ and R⁹ are each independently hydroxy, alkoxy, oraminoalkyl; or R⁸ and R⁹ together with the boron atom to which they areattached form a 5 to 14-membered ring, said ring comprising carbon atomsand optionally one or more heteroatoms which can be N or O; said ringmay be optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR¹³,C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyl each of which may beoptionally substituted with one or more substituents independentlyselected from the group consisting of hydroxy, amino, halogen, C(O)OH,C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹); R¹⁰ and R¹¹ are each independentlyhydrogen or C₁₋₆alkyl; R¹³ is alkoxy; X is alkylene or —O-alkylene,wherein alkylene is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰ and C₃₋₆cycloalkyl; or a pharmaceutically acceptable saltthereof, and a second therapeutic agent selected from the groupconsisting of an HCV NS2 protease inhibitor, an HCV NS3/4A proteaseinhibitor, an HCV NS3 helicase inhibitor, an HCV NS4B replication factorinhibitor, an HCV NS5A replication factor inhibitor, an HCV NS5Bpolymerase inhibitor, an HCV entry inhibitor, an HCV internal ribosomeentry site inhibitor, a microsomal triglyceride transfer proteininhibitor, an α-glucosidase inhibitor, a caspase inhibitor, acyclophilin inhibitor, an immunomodulator, a metabolic pathwayinhibitor, an interferon, and a nucleoside analogue.
 3. A compositioncomprising administering a compound of Formula (II):

wherein: R is independently selected from the group consisting ofhalogen, C₁₋₆alkyl, alkoxy, —CN, —CF₃, —O—C₆₋₁₀aryl optionallysubstituted by halogen, and —O-heteroaryl optionally substituted byhalogen; R¹ is —C(O)OH, —C(O)NHR⁵ or heterocyclyl; R² is C₁₋₆alkyl,C₃₋₆cycloalkyl, —C(H)F₂, —CF₃, or —OR⁶; R³ is —S(O)₂R⁷ or —C(O)R⁷; R⁴ is(a) heteroaryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; (b)C₆₋₁₀aryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; Het is a 5 or 6-memberedmonocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclicring system any ring of which is either saturated, partially saturatedor unsaturated, which may be optionally benzofused if monocyclic orwhich may be optionally spiro-fused, and wherein each Het consists ofone or more carbon atoms and one boron atom and one or more oxygenatoms; one boron atom, one oxygen atom, and one nitrogen atom; or oneboron atom and one or more nitrogen atoms; R⁵ is hydrogen, C₁₋₆alkyl,hydroxy, or —OR⁶; R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁷ is C₁₋₆alkyl,hydroxyalkyl, or aminoalkyl; R⁸, R⁹, and R¹² are each independentlyhydroxy, alkoxy, or aminoalkyl; or R⁸ and R⁹ or R⁸, R⁹, and R¹² togetherwith the boron atom to which they are attached form a 5 to 14-memberedring, said ring comprising carbon atoms and optionally one or moreheteroatoms which can be N or O; said ring may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH,C(O)OXOR¹³, C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyl each ofwhich may be optionally substituted with one or more substituentsindependently selected from the group consisting of hydroxy, amino,halogen, C(O)OH, C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹); R¹⁰ and R¹¹ are eachindependently hydrogen or C₁₋₆alkyl; R¹³ is alkoxy; X is alkylene or—O-alkylene, wherein alkylene is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰ and C₃₋₆cycloalkyl; m is 1, 2, or 3;or a pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue.
 4. A composition comprising a compound of Formula(IIB):

wherein: R is F or Cl; R¹ is —C(O)NHR⁵; R² is C₃₋₆cycloalkyl; R³ is—S(O)₂R⁷; R⁴ is (a) heteroaryl substituted with B(R⁸)(R⁹) or XB(R⁸)(R⁹),and optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂,—CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH,—C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl; (b) C₆₋₁₀aryl substituted withB(R⁸)(R⁹), or XB(R⁸)(R⁹), and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; Het is a 5 or 6-memberedmonocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclicring system any ring of which is either saturated, partially saturatedor unsaturated, which may be optionally benzofused if monocyclic orwhich may be optionally spiro-fused, and wherein each Het consists ofone or more carbon atoms and one boron atom and one or more oxygenatoms; one boron atom, one oxygen atom, and one nitrogen atom; or oneboron atom and one or more nitrogen atoms; R⁵ is C₁₋₆alkyl; R⁶ isC₁₋₆alkyl or C₃₋₆cycloalkyl; R⁷ is C₁₋₆alkyl, hydroxyalkyl, oraminoalkyl; R⁸ and R⁹ are each independently hydroxy, alkoxy, oraminoalkyl; or R⁸ and R⁹ together with the boron atom to which they areattached form a 5 to 14-membered ring, said ring comprising carbon atomsand optionally one or more heteroatoms which can be N or O; said ringmay be optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR¹³,C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyl each of which may beoptionally substituted with one or more substituents independentlyselected from the group consisting of hydroxy, amino, halogen, C(O)OH,C(O)N(R¹⁰)(R¹¹), and)N(R¹⁰ (R¹¹); R¹⁰ and R¹¹ are each independentlyhydrogen or C₁₋₆alkyl; R¹³ is alkoxy; X is alkylene or —O-alkylene,wherein alkylene is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰ and C₃₋₆cycloalkyl; or a pharmaceutically acceptable saltthereof, and a second therapeutic agent selected from the groupconsisting of an HCV NS2 protease inhibitor, an HCV NS3/4A proteaseinhibitor, an HCV NS3 helicase inhibitor, an HCV NS4B replication factorinhibitor, an HCV NS5A replication factor inhibitor, an HCV NS5Bpolymerase inhibitor, an HCV entry inhibitor, an HCV internal ribosomeentry site inhibitor, a microsomal triglyceride transfer proteininhibitor, an α-glucosidase inhibitor, a caspase inhibitor, acyclophilin inhibitor, an immunomodulator, a metabolic pathwayinhibitor, an interferon, and a nucleoside analogue.
 5. A pharmaceuticalcomposition comprising a compound of Formula (II):

wherein: R is independently selected from the group consisting ofhalogen, C₁₋₆alkyl, alkoxy, —CN, —CF₃, —O—C₆₋₁₀aryl optionallysubstituted by halogen, and —O-heteroaryl optionally substituted byhalogen; R¹ is —C(O)OH, —C(O)NHR⁵ or heterocyclyl; R² is C₁₋₆alkyl,C₃₋₆cycloalkyl, —C(H)F₂, —CF₃, or —OR⁶; R³ is —S(O)₂R⁷ or —C(O)R⁷; R⁴ is(a) heteroaryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; (b)C₆₋₁₀aryl substituted with B(R⁸)(R⁹), XB(R⁸)(R⁹), OXB(R⁸(R⁹),B⁻(R⁸)(R⁹)(R¹²), XB(R⁸)R⁹)(R¹²) or Het optionally substituted withhydroxy or hydroxyalkyl; and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; Het is a 5 or 6-memberedmonocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclicring system any ring of which is either saturated, partially saturatedor unsaturated, which may be optionally benzofused if monocyclic orwhich may be optionally spiro-fused, and wherein each Het consists ofone or more carbon atoms and one boron atom and one or more oxygenatoms; one boron atom, one oxygen atom, and one nitrogen atom; or oneboron atom and one or more nitrogen atoms; R⁵ is hydrogen, C₁₋₆alkyl,hydroxy, or —OR⁶; R⁶ is C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁷ is C₁₋₆alkyl,hydroxyalkyl, or aminoalkyl; R⁸, R⁹, and R¹² are each independentlyhydroxy, alkoxy, or aminoalkyl; or R⁸ and R⁹ or R⁸, R⁹, and R¹² togetherwith the boron atom to which they are attached form a 5 to 14-memberedring, said ring comprising carbon atoms and optionally one or moreheteroatoms which can be N or O; said ring may be optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH,C(O)OXOR¹³, C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyl each ofwhich may be optionally substituted with one or more substituentsindependently selected from the group consisting of hydroxy, amino,halogen, C(O)OH, C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹); R¹⁰ and R¹¹ are eachindependently hydrogen or C₁₋₆alkyl; R¹³ is alkoxy; X is alkylene or—O-alkylene, wherein alkylene is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁶R¹¹, —NHC(O)R¹⁶ and C₃₋₆cycloalkyl; m is 1, 2, or 3;or a pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from the group consisting of an HCV NS2 proteaseinhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicaseinhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5Areplication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCVentry inhibitor, an HCV internal ribosome entry site inhibitor, amicrosomal triglyceride transfer protein inhibitor, an α-glucosidaseinhibitor, a caspase inhibitor, a cyclophilin inhibitor, animmunomodulator, a metabolic pathway inhibitor, an interferon, and anucleoside analogue, or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier.
 6. A pharmaceutical compositioncomprising a compound of Formula (IIB):

wherein: R is F or Cl; R¹ is —C(O)NHR⁵; R² is C₃₋₆cycloalkyl; R³ is—S(O)₂R⁷; R⁴ is (a) heteroaryl substituted with B(R⁸)(R⁹) or XB(R⁸)(R⁹),and optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁₋₆alkoxy, —C(H)F₂,—CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂, —C(O)OH,—C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰,C₃₋₆cycloalkyl, and heterocyclyl; (b) C₆₋₁₀aryl substituted withB(R⁸)(R⁹), or XB(R⁸)(R⁹), and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, —C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl,aminoalkyl, —C(O)NH₂, —C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN,—OCF₃, —OR⁶, —NR¹⁰R¹¹, —NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; or(c) Het optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰, C₃₋₆cycloalkyl, and heterocyclyl; Het is a 5 or 6-memberedmonocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclicring system any ring of which is either saturated, partially saturatedor unsaturated, which may be optionally benzofused if monocyclic orwhich may be optionally spiro-fused, and wherein each Het consists ofone or more carbon atoms and one boron atom and one or more oxygenatoms; one boron atom, one oxygen atom, and one nitrogen atom; or oneboron atom and one or more nitrogen atoms; R⁵ is C₁₋₆alkyl; R⁶ isC₁₋₆alkyl or C₃₋₆cycloalkyl; R⁷ is C₁₋₆alkyl, hydroxyalkyl, oraminoalkyl; R⁸ and R⁹ are each independently hydroxy, alkoxy, oraminoalkyl; or R⁸ and R⁹ together with the boron atom to which they areattached form a 5 to 14-membered ring, said ring comprising carbon atomsand optionally one or more heteroatoms which can be N or O; said ringmay be optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR¹³,C(O)N(R¹⁰)(R¹¹), N(R¹⁰)(R¹¹), and C₃₋₆cycloalkyl each of which may beoptionally substituted with one or more substituents independentlyselected from the group consisting of hydroxy, amino, halogen, C(O)OH,C(O)N(R¹⁰)(R¹¹), and N(R¹⁰)(R¹¹); R¹⁰ and R¹¹ are each independentlyhydrogen or C₁₋₆alkyl; R¹³ is alkoxy; X is alkylene or —O-alkylene,wherein alkylene is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,—C(H)F₂, —CF₃, C₁₋₆alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH₂,—C(O)OH, —C(O)NHR⁵, —S(O)₂R⁶, —S(O)₂NH₂, —CN, —OCF₃, —OR⁶, —NR¹⁰R¹¹,—NHC(O)R¹⁰ and C₃₋₆cycloalkyl; or a pharmaceutically acceptable saltthereof, and a second therapeutic agent selected from the groupconsisting of an HCV NS2 protease inhibitor, an HCV NS3/4A proteaseinhibitor, an HCV NS3 helicase inhibitor, an HCV NS4B replication factorinhibitor, an HCV NS5A replication factor inhibitor, an HCV NS5Bpolymerase inhibitor, an HCV entry inhibitor, an HCV internal ribosomeentry site inhibitor, a microsomal triglyceride transfer proteininhibitor, an α-glucosidase inhibitor, a caspase inhibitor, acyclophilin inhibitor, an immunomodulator, a metabolic pathwayinhibitor, an interferon, and a nucleoside analogue, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 7. The method according to claim 1, wherein thesecond therapeutic agent is an interferon.
 8. The method according toclaim 7 wherein the interferon is selected from the group consisting ofinterferon alfa-2a, peginterferon alfa-2a, interferon alfa-2b,peginterferon alfa-2b, an interferon alfa-2b analogue, interferonalpha-2b XL, interferon alfacon-1, interferon alfa-n1, interferon omega,HDV-interferon, peginterferon beta, peginterferon lambda, andinterferon-alpha5.
 9. The method according to claim 8 wherein theinterferon is selected from the group consisting of interferon alfa-2a,peginterferon alfa-2a, interferon alfa-2b, peginterferon alfa-2b, aninterferon alfa-2b analogue, interferon alfacon-1, and interferonalfa-n1.
 10. The method according to claim 7 further comprisingadministering a nucleoside analogue.
 11. The method according to claim10 wherein the nucleoside analogue is ribavirin.
 12. The methodaccording to claim 1, wherein the compound of Formula (II) is selectedfrom the group consisting of:(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid;(2-Chloro-4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid;4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronicacid;3-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronicacid;4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronicacid;4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorophenylboronicacid;4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronicacid;6-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)pyridin-3-ylboronicacid;(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronicacid;(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(trifluoromethyl)phenyl)boronicacid;(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2,6-difluorophenyl)boronicacid;(2-cyano-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronicacid6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylicacid;(4-(N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-6-yl)methylsulfonamido)-2-chlorophenyl)boronicacid;6-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(methylsulfonyl)phenyl)boronicacid;1-(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)-4-methyl-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide;((4-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronicacid;((2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronicacid;5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;(4-(N-(2-(4-Chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-cyanophenyl)boronicacid;5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide;(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronicacid;5-Cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-4-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;(3-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronicacid;6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 1;6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,enantiomer 2;5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-6-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;and pharmaceutically acceptable salts thereof.
 13. The method accordingto claim 1, wherein the compound of Formula (II) is a compound havingthe structure: